Identifying and Regulating Carcinogens

November 1987

NTIS order #PB88-136999
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Identifying and Regulating Carcinogens,

OTA-BP-FI-42 (Washington, DC: U.S. Government Printing Office, November 1987).

Library of Congress Catalog Card Number 87-619859

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, DC 20402-9325

(order form can be found in the back of this report)
Foreword

Congressional interest in reducing and preventing exposures to carcinogenic chemicals has been expressed in statutes authorizing the regulation of food additives, drugs,

consumer products, occupational exposures, air and water pollutants, drinking water

contaminants, pesticides, toxic chemicals, and hazardous wastes. OTA’s previous work

on these topics includes our 1981 report, Technologies for Determining Cancer Risks

From the Environment, as well as other OTA reports describing technologies for controlling environmental and occupational hazards.

This background paper was requested by the House Government Operations Committee and its Subcommittee on Intergovernmental Relations and Human Resources.

In it, OTA describes policies issued by Federal agencies concerning the identification,

assessment, and regulation of carcinogenic chemicals; the chemicals that have been regulated because of carcinogenic risk; the Federal Government’s carcinogenicity testing program; and the results of OTA’s analysis of the extent of agency action on chemicals

determined to be carcinogenic.

This background paper covers 16 different Federal agencies, programs, and activities: the Occupational Safety and Health Administration, the Mine Safety and Health

Administration, the National Institute for Occupational Safety and Health, the Consumer Product Safety Commission, and the Food and Drug Administration, including

its activities on food and color additives, human drugs, and animal drugs. For the Environmental Protection Agency (EPA), this background paper discusses the Carcinogen Assessment Group, as well as EPA standard-setting on carcinogens under the Clean

Air Act, Clean Water Act, Safe Drinking Water Act, Toxic Substances Control Act,

the Federal Insecticide, Fungicide, and Rodenticide Act, Resource Conservation and

Recovery Act, and the Comprehensive Environmental Response, Compensation, and

Liability Act. Finally, the activity of the National Toxicology Program is described.

A large number of Federal agency personnel and others assisted in providing information for this background paper. We thank them for their assistance. Key OTA

staff involved with this background paper were Karl Kronebusch, Sylvia Tognetti, and

Neil Holtzman. Carl Cranor worked on this background paper while serving as a Congressional Fellow of the American Philosophical Association.

J oHN H. G IBBON S

Director
OTA Project Staff for Identifying and Regulating Carcinogens

Roger C. Herdman, Assistant Director, OTA

Division of Health & Life Sciences

Clyde J. Behney, Health Program Manager

Karl Kronebusch, Study Director

Hellen Gelband, Director, Special Projects Office

Sylvia Tognetti, Research Assistant

Neil Holtzman, Senior Analyst

Carl Cranor, Fellow

Brigitte M. Duffy, Research Assistant’

Virginia Cwalina, Administrative Assistant

Carol Ann Guntow, PC Specialist

Karen T. Davis, Secretary/Word Processor Specialist

Carolyn Martin, Clerical Assistant

‘Since August 1987.

iv
Contents

Chapter 1.

Chapter 2.

Chapter 3.

Chapter 4.

Chapter 5.

Page

Introduction and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Policies for Testing, Assessing, and Regulating Carcinogens . . . . . . . . . . . . 23

Federal Agency Assessment and Regulation of Carcinogens . . . . . . . . . . . . . 75

The National Toxicology Program . . . . . . . . . . . . . . . . . . . .

Agency Responses to the Annual Report on Carcinogens

NCI/NTP Test Results . . . . . . . . . . . . .

Appendix A.

Appendix B.

Appendix C.

Appendix D.

References . .

Statutory Authority for Regulating

Chemicals Listed in Annual Report

and NCI/NTP Test Results . . . . . . .

Acknowledgments . . . . . . . . . . . . . . .

Acronyms . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . .

Carcinogens . . .

on Carcinogens

. . . . . . . . . . . . . .

. . . . . . . . . . . . . .

. . . . . . . . . . . . . .

. . . . . . . . . . . . . .

. . .

. . .

. . .

. . .

. . .

. . .

. . . . . . . . . . . . . . . 145

and

. . . . . . . . . . . . . . . 169

. . . . . . . . . . . . . . . 199

. . . . . . . . . . . . . . . 221

. . . . . . . . . . . . . . . 228

. . . . . . . . . . . . . . 

. 231

. . . . . . . . . . . . . . . 233
Chapter 1

Introduction and Summary
CONTENTS

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Summary .. .. . $ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Agency Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Required Animal Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Guidelines for Testing Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Risk Assessment Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Carcinogen Assessment Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Federal Assessment and Regulation of Carcinogens . . . . . . . . . . . . . . . . . . . . . . . . 9

Type of Evidence: Human or Animal Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

The National Toxicology Program (NTP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l6

Regulatory Responses to NCI/NTP Test Results and the Annual Report . . . . . 18

Future Improvements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figures

Figure No. Page

l-1. Elements of Risk Assessment and Risk Management. . . . . . . . . . . . . . . . . . . . . 8

l-2. Agency Actions on Annual Report and Positive NCI/NTP Chemicals . . . . . 20
Chapter 1

Introduction and Summary

INTRODUCTION

Over the years, laws have been enacted to protect the health of Americans, with particular emphasis on protection against cancer. By and large,

these laws provide for reducing or eliminating exposures to external chemical carcinogens with

which people come into contact—in the food supply; in drinking water; in pharmaceutical drugs

and other consumer products; in work environments; in ambient air, water, and soil. Most cases

of cancer, however, are not caused by these types

of carcinogenic exposures.

Instead, according to the best interpretation of

the evidence currently available, most result from

“lifestyle” factors, of which the details are only

slowly becoming clear. One—tobacco smoking—

stands out the clearest of all, and alone is the cause

of more than one-third of all deaths from cancer

each year in the United States. The more poorly

defined lifestyle factors include such items as overall dietary balance and aspects of sexual behavior;

others, slightly better defined, include exposure

to sunlight (see OTA 1981 for a fuller discussion

of causes of cancer). In addition to lifestyle factors, viruses are potentially great, but currently

unquantifiable, contributors to the overall cancer burden. Nevertheless, those carcinogenic

chemicals that can be identified specifically and

can be controlled are important for those very reasons: they are avoidable. And often, unlike cigarette smoking, exposure to them is involuntary.

Furthermore, the potential for introducing new,

potent, carcinogens is very real.

For the laws addressing chemical carcinogens

to be effective, there must be means of identifying substances that have caused, or would cause,

human beings to get cancer. Once the substances

have been identified, regulatory decisions can be

made about whether and how to control exposures. Both the process for finding out which substances already in the human environment are

causing cancer in the population (through epidemiologic studies) and the process for predicting carcinogenicity in humans before people are

exposed (by testing in the laboratory and in experimental animals) are imperfect, and interpretation of the results of such studies is contentious.

While efforts to develop improved methods for

identifying carcinogens continue, current and past

regulatory decisions have, of necessity, embodied

many untested and some untestable assumptions.

This OTA background paper responds to a request from the House Committee on Government

Operations and its Subcommittee on Intergovernmental Relations and Human Resources to examine Federal activity in testing chemicals for

carcinogenicity and the use of test results by regulatory agencies.

In this background paper, OTA addresses the

following specific questions:

●

●

●

What policies for regulating carcinogens have

Federal agencies adopted? What guidance do

these policies provide about identifying,

assessing, and regulating chemical carcinogens? What kind of evidence, human or animal, do the agencies require to identify a

chemical qualitatively as carcinogenic? How

do the agencies intend to conduct quantitative risk assessments?

What chemicals have actually been regulated? What evidence provided the basis for

these regulations? How long does the regulatory process take?

How is Federal carcinogenicity testing organized? How are chemicals chosen for such

testing? After the chemicals are tested, are

the chemicals that test positive regulated?

Have agencies regulated the chemicals listed

in the Federal Government’s Annual Report

on Carcinogens?

Chapter 2 of this background paper compares

the formal Federal policies for identifying and

assessing the risks from carcinogenic chemicals.

Chapter 3 lists the carcinogenic chemicals that

have been regulated by each Federal regulatory

agency. Federal agencies with the greatest roles

in regulating chemical carcinogens are the Food

and Drug Administration (FDA) for foods, cos3
4

metics, and human and animal drugs; the Occupational Safety and Health Administration (OSHA)

for worker exposure in most industries; the Mine

Safety and Health Administration (MSHA) for

worker exposure in mines; the Consumer Product Safety Commission (CPSC) for consumer

products; and the Environmental Protection

Agency (EPA). EPA is charged with regulating air

pollutants under the Clean Air Act (CAA); water

pollutants under Clean Water Act (CWA); drinking water contaminants under the Safe Drinking

Water Act (SDWA); pesticides under the Federal

Insecticide, Fungicide, and Rodenticide Act

(FIFRA); toxic chemicals under the Toxic Substances Control Act (TCSA); and hazardous

wastes under the Resource Conservation and Recovery Act (RCRA) and the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA).

Chapter 4 describes the National Toxicology

Program (NTP), the home of the Federal testing

program, and its carcinogenicity testing. Chapter 5 examines the regulatory responses to positive results from Federal carcinogenicity bioassays

and to the chemicals listed in the Annual Report

SUMMARY

Agency Policies

Over the last decade, several Federal agencies

have issued guidelines and policies detailing how

they intend to identify, evaluate, and regulate carcinogens. These guidelines encompass the design

of animal carcinogenicity bioassays, the interpretation of data from human and animal studies,

and the assumptions that should or will be made

when assessing human risk from such studies.

The assumptions in these documents represent

scientific views and policy judgments about carcinogen assessment. Some assumptions are made

because, though appropriate data might be obtained with current techniques, the data are simply not available in a particular case. Other more

general assumptions take the place of experimental

evidence that may be developed with further research. Finally, some assumptions are employed

because of ethical considerations and the inheron Carcinogens. Appendix A describes the Federal statutes that have been most important in regulating carcinogenic chemicals.

The scope of this background paper is limited

to “chemicals” that have been tested, listed, or regulated by the Federal Government for carcinogenicity. The term “chemical” is used broadly here

to encompass substances, mixtures, groups of substances, and exposures. This background paper

does not examine the regulation of radiation

sources licensed by the Nuclear Regulatory Commission, electronic radiation (including, for example, x-ray machines, which are regulated by

FDA), ultraviolet radiation, alcohol, and tobacco.

Depending on statutory mandate, Federal regulatory decisions can be based on such factors as

control technologies and costs, in addition to

risks. Agency procedures for developing information on these factors will not be discussed in this

background paper. Moreover, while very important, other related efforts not covered here are

those of industry and the private sector to test

chemicals for carcinogenicity and implement

voluntary controls to reduce exposures to carcinogens.

ent limits of experimental methods. The use of

assumptions, the frequent absence of data, the

potential economic implications of government

regulation, and underlying political disputes about

the desirability of regulation, combine to make

the assessment of carcinogenicity and the development of corresponding regulations subjects of

intense debates.

It is now common to distinguish between risk

assessment and risk management: risk assessment

characterizes the adverse health effects of human

exposures to environmental hazards; risk management is the choosing of regulatory options.

Both risk assessment and risk management incorporate policy choices and reflect the values of the

risk assessors and managers. Some agencies have

attempted to establish separate staffs for the two

tasks, but this separation does not eliminate the

need to make policy choices about the assumptions used in risk assessments.
5

The values and policy preferences of decisionmakers, risk assessors, and representatives of industry, labor unions, environmental organizations, and public interest groups often differ.

Scientists disagree about the nature of scientific

evidence. These differences explain some of the

past controversies over the regulation of specific

carcinogenic chemicals and the development of

agency policies.

In 1983, a committee of the National Research

Council recommended the development of uniform guidelines for conducting risk assessments.

The committee described several advantages and

disadvantages of such guidelines. They have the

advantages of promoting quality control, consistency, predictability, public understanding,

administrative efficiency, and improvements in

methods. In addition, guidelines serve an important role within agencies in training new staff in

agency practices. The potential disadvantages of

such guidelines include oversimplification, inappropriate mixing of scientific knowledge with risk

assessment policy, misallocation of agency resources to the task of developing guidelines, and

insensitivity to scientific developments. Some

have hoped that policies for assessing and regulating carcinogens would speed regulatory activity. Others have tried to use such policies to

change the direction of risk assessment and regulation.

While much effort has been devoted to developing guidelines and policies for carcinogen

assessment and regulation, it is not clear how

much effect they have actually had. They do provide points of reference for discussions on particular regulatory issues. Nevertheless, while there

are important disagreements among regulatory

agencies, industries, and other groups on general

issues, many disagreements concern interpretations of evidence in particular cases. Everyone

may agree, for example, that animal data can be

used to identify potential human carcinogens, yet

they may disagree about the applicability of results from particular animal experiments in assessing particular chemicals, especially commercially

important ones. Adoption of general guidelines

cannot resolve these specific disputes.

Agency policies and guidelines have varied considerably in their flexibility, formality, and comprehensiveness. They have also evolved, generally becoming more complex and detailed.

This background paper considers two distinct,

but related, types of guidelines: agency requirements for animal carcinogenicity studies; and

agency policies on identifying, assessing, and regulating carcinogens.

Required Animal Testing

FDA and EPA have required industry to conduct carcinogenicity testing of food and color additives, animal drugs, animals, human drugs, pesticides, and toxic substances.

FDA requires carcinogenicity testing for a proposed food additive only if it falls into certain

chemical categories and its expected concentration in food exceeds specified levels. For an animal drug, testing may be required depending on

the expected extent of its use in animals, the levels

of drug residues, and the potential toxicity of the

drug as determined from chemical structure,

short-term tests, and other data. FDA requires

carcinogenicity testing for new human drugs that

are expected to have chronic or widespread use,

although this requirement has not been applied

to drugs marketed prior to 1968. For some of these

older drugs, which are used widely today, FDA

has requested studies from NTP rather than from

drug manufacturers.

EPA may require animal carcinogenicity studies

of pesticides when they generate some toxicologic

concern, when they will be used on food, or when

their use will result in significant human exposure.

Considerable delays have occurred in requiring

test data on pesticides marketed prior to 1972. Under TSCA, EPA may require testing for new

chemicals or for existing chemicals.

Guidelines for Testing Protocols

OTA compared the bioassay study designs for

suspected carcinogens that are specified by several Federal agencies. FDA and EPA have issued

guidelines for the design of toxicologic studies, in-
6

eluding those of carcinogenicity. FDA has relied

on nonregulatory guidelines, such as its “Red

Book,” for studies required of new food and color

additives. For human drugs, a joint workshop

sponsored by FDA and the Pharmaceutical Manufacturers’ Association (PMA) discussed the design of studies. Although FDA decided not to issue guidelines under its own name, the guidelines

were published by PMA. EPA issued as regulations separate testing guidelines for pesticides and

for toxic substances. The National Cancer Institute (NCI) and NTP test guidelines were also considered in this OTA comparison.

Federal agency guidelines are generally consistent about major features of the study design. They

specify testing in two animal species, which in

practice are usually rats and mice. The two oldest guidelines (those of NCI and PMA) require at

least two dose groups in addition to a control

group. All other guidelines suggest the use of three

dose groups and a control group. The guidelines

agree that to maximize the sensitivity of a study

in detecting carcinogenic effects, the highest dose

in the study must be set as high as possible without shortening the animals’ lives because of noncarcinogenic toxic effects.

Risk Assessment Policies

OTA also compared Federal agencies’ policies

on identifying and assessing carcinogens. These

policies were issued under a variety of circumstances and are organized in different ways. In

some cases, the policies are relatively informal

statements of current scientific understanding

about how carcinogens might be identified. In

other cases, they constitute formally adopted regulations, specifying how an agency will identify

carcinogens and limiting the kinds of arguments

and evidence to be considered in specific regulatory proceedings. In between these two extremes,

some documents outline an agency’s standard procedures and discuss problematic areas of interpretation, including the inference assumptions that

the agency will use.

Several agency policies have taken a regulatory

form, for example, OSHA’s 1980 policy. OSHA

intended to collect evidence and testimony on

“generic” issues in carcinogen identification and

regulation, make decisions on these issues, and

then rely on these decisions and presumptions in

future proceedings. The policy might be termed

a “presumption-rebuttal” approach, providing

strong presumptions and limited room for rebuttal. The framers of this policy hoped it would limit

debate in subsequent regulatory proceedings and

thereby speed carcinogen regulation. That hope

has not been realized. Two carcinogens with occupational exposures, ethylene oxide and asbestos, have been regulated since the publication

of OSHA’s policy.

CPSC attempted to adopt carcinogen assessment guidelines in 1978. CPSC was sued, and the

guidelines were struck down by a reviewing court.

Subsequent to this decision, CPSC formally withdrew its policy.

FDA has been working on a regulatory definition of allowable animal drug residues in human

food since 1973. This definition specifies how sensitive an analytic technique must be, hence the

definition is called “sensitivity of method” (SOM).

It was first proposed in 1973, made final in 1977,

challenged in court and sent back to FDA, reproposed in 1979, then proposed for a third time in

1985. The final rule has still not been issued.

Other agency policies provide guidelines for

conducting risk assessments. EPA’s 1976 “interim”

guidelines and its 1986 carcinogen risk assessment

guidelines are examples of this approach, which

discusses scientific issues, sets forth flexible assumptions, and specifies an analysis based on the

weight of the evidence.

A 1979 Interagency Regulatory Liaison Group

(IRLG) policy and a 1985 guideline issued by the

White House Office of Science and Technology

Policy (OSTP) both discussed current knowledge

of carcinogenesis and related risk assessment techniques. These documents are important because

they represent the results of extensive discussions

among scientists from many agencies. One goal

of these discussions was to develop a consensus

among the agencies on these issues.

Not all agency programs have adopted policies

on risk assessment. For example, FDA does not

have a formal risk assessment policy on food and

color additives. However, FDA’s Center for Food
7

Safety and Applied Nutrition has established a

formal committee for considering evidence on the

carcinogenicity of food and color additives. FDA

has published a policy on regulating additives with

carcinogenic impurities and has developed a policy incorporating a de minimis approach to regulating the safety of food and color additives. For

evaluating the safety of human drugs, FDA requires different kinds of tests depending on the

expected duration of human use of the drug, but

it has never issued guidelines for evaluating or

assessing animal carcinogenicity test results. It

does provide guidance, however, on preparing

data for statistical analysis.

Carcinogen Assessment Policies

A National Research Council committee divided

risk assessment into four distinct parts: hazard

identification, dose-response assessment, exposure

assessment, and risk characterization (137). Hazard identification is the qualitative identification

of a substance as a human or animal carcinogen.

In dose-response assessment, the relationship between the level of exposure or the dose and the

incidence of disease is described. The two most

important aspects of the second step are extrapolating from information on incidence at high

doses to predict incidence at lower doses and, in

the case of risk assessments based on animal data,

converting animal doses into equivalent human

doses. Exposure assessment estimates the frequency, duration, and intensity of human exposures to the agent in question. Finally, risk

characterization relies on information from both

dose-response and exposure assessments to estimate the expected risk, as well as to explain the

nature of the risk and any uncertainties in assessing it.

Figure 1-1 illustrates these steps, which eventually lead to information useful for risk management decisions. Each step involves some uncertainty, owing either to inadequate data on the

particular agent or to uncertainty about its mechanisms of toxicity.

Hazard Identification

In many situations of regulatory interest, there

are few toxicity data of any sort. When data are

available, the agencies value epidemiologic studies

as the most conclusive evidence for human carcinogenicity, presume that substances found to

be carcinogenic in animals in long-term bioassays

present carcinogenic hazards to humans, and use

short-term test results as supportive information.

Analyses of structure-activity relationships (analyses based on the structural similarity of a substance to other known carcinogens) are used

mostly when there are no other data (e.g., to identify new chemicals that should have additional

testing prior to large-scale manufacture).

All Federal policies accept the use of animal

data in predicting human effects. While it is not

known with certainty that all animal carcinogens

are also human carcinogens, most well-studied human carcinogens show some evidence of carcinogenicity in animals.

While agencies accept animal data, determining exactly what evidence demonstrates that a

substance is an animal carcinogen is more complex. Generally, the agencies accept data derived

from use of the maximum tolerated dose, and then

use the increased incidence of malignant or benign tumors to demonstrate carcinogenicity. Policies usually state that positive results in animals

outweigh negative epidemiologic results, and that

positive results in one species outweigh negative

results in another.

Dose-Response Assessment

Prior to 1970, there was considerable doubt

about the utility of quantitative assessments. During the 1970s and 1980s, the agencies began using

these assessments for carcinogens. In 1973, FDA

specified the use of quantitative risk assessment

in the proposed SOM for evaluating animal drugs.

In 1978 and 1979, FDA conducted risk assessments

for the environmental contaminants aflatoxins

and polychlorinated biphenyls (PCBS). FDA first

used risk assessment to determine the risk of carcinogenic impurities of color additives in 1982 and

of food and color additives themselves in 1985 and

1986, The first EPA risk assessment, in 1975, concerned vinyl chloride. In 1976, EPA established

its Carcinogen Assessment Group and published

its “interim” guidelines on risk assessment. CPSC’s

first use of risk assessment came with its evalua-
8

Figure 1-1 .—Elements of Risk Assessment and Risk Management

I

I

I

SOURCE: National Academy of Sciences/National Research Council, Risk Assessment in the Federal Government: Managing the Process (Washington, DC: National

Academy Press, 1983).

tion of tris(2,3-dibromopropyl)phosphate (Tris)

in 1977. While OSHA had first prepared a quantitative risk assessment in 1976 for worker exposure

to coke oven emissions, it resisted calls for increased use of these assessments until the Supreme

Court’s 1980 decision on the benzene standard.

Today, although there are still many uncertainties associated with quantitative risk assessment,

all of these agencies use it.

The agencies all assume that human risk estimates can be derived from animal data, that carcinogenic chemicals do not have no-effects thresholds, and that risk estimates should be based on

results from the most sensitive animal species. All

the agencies use mathematical models that assume

low-dose linearity for extrapolating from the doses

tested in the animal experiment to the doses of

regulatory interest, although they differ on the

mathematical technique to use, whether the focus should be on the “upper confidence limit” or

the “maximum likelihood estimate, ” and the

method of converting animal doses into human

doses. The general approach is to develop risk

estimates with assumptions designed to err on the

side of safety. The agency policies do not distinguish among chemicals thought to have different

mechanisms of action (e.g., between “initiators”

and “promoters”). The agencies are only beginning to explore the use of pharmacokinetic modeling techniques, and thus have not discussed these

in detail in their policies.

Exposure Assessment

Agency policies give much less detailed guidance on how human exposures to specific chemicals should be estimated. While EPA has issued

exposure guidelines, the predominant approach

in those guidelines and in actual agency practice

is to make evaluations case by case. The lack of

detailed guidelines does not diminish the great importance of considering exposure in estimating human risk.
9

Risk Characterization

Several policies discuss risk characterization,

mentioning alternative ways to describe estimated

risk and various sources of uncertainty. Some policies also specify a method of classifying carcinogens, for example, by the weight of evidence for

carcinogenicity. Considering the weight of evidence, that is, using all available information on

a chemical’s effects, has received more attention

in recent policies.

Federal Assessment and Regulation

of Carcinogens

Federal statutes authorize agencies to set exposure standards, residue limits, tolerances, and

emissions standards for carcinogenic chemicals

found in air, water, food, and the workplace.

Some statutes authorize or require the outright

banning of carcinogenic substances or products

containing them; in other cases, agencies may set

rules for a product’s use.

Under this authority, a number of carcinogens

have been regulated, although the agencies have

not acted on all of the exposures known to present

carcinogenic risk. While some time is required to

prepare the analyses necessary for regulatory action and to respond to public comment, there have

also been lengthy delays between knowing the

outcome of human epidemiologic studies or animal bioassays and publishing proposed regulations, and delays between the publication of proposed and final rules. Regulations on carcinogens

have frequently been challenged in court by industry, labor unions, environmental organizations, or other groups. In some cases the courts

have ruled that the agencies exceeded their authority, although in other cases the courts have compelled the agencies to act.

Many chemical exposure limits set by the government or recommended by private individuals

and organizations were established primarily to

protect people from noncarcinogenic toxicities—

effects that manifest themselves at the time of exposure or shortly thereafter. But cancer is an insidious disease. People can be exposed to carcinogens at levels that do not cause any immediately

apparent adverse effects. These exposures, however, can crucially injure individual cells, leading to cancer many years later. Thus, regulatory

standards to protect the public from carcinogen

exposures will need to be set at levels much lower

than those designed to protect against acute toxicities.

In general, a standard that reduces exposures

based on concern for one health effect will do so

for all health effects associated with that chemical. But a standard based on noncarcinogenic toxicities may not reduce exposures sufficiently to

protect against cancer. Significantly, many Federal standards regulating carcinogenic chemicals

were set originally to protect against noncarcinogenic toxicities and have not been updated to take

account of carcinogenic effects.

OSHA

Congress passed the Occupational Safety and

Health Act in 1970. In 1971, OSHA adopted a

large number of startup standards, setting exposure limits on about 400 specific chemicals.

These exposure standards consisted largely of the

1968 recommendations of the American Conference of Governmental Industrial Hygienists

(ACGIH) and had been developed primarily to

protect workers from noncarcinogenic toxicities.

While the ACGIH recommendations are updated

annually, OSHA standards are not.

From 1972 to 1986, OSHA issued health standards covering 22 carcinogens, many of which had

been regulated by the 1971 standards. Most of

these carcinogen standards have aroused controversy. Of 9 final actions on carcinogens regulated individually (including 2 on asbestos), 7 resulted in court challenges. In OSHA’s regulation

of a group of 14 carcinogens, the final standards

for 2 chemicals were challenged. Permanent standards for 2 chemicals were struck down as a result

of such challenges.

National Institute for Occupational

Safety and Health (NIOSH)

One role of NIOSH is to identify substances

that pose potential health problems and recommend exposure levels to OSHA. However, OSHA

has not responded to many NIOSH recommen-
10

dations. Since 1971, NIOSH recommendations

have addressed 71 different chemicals or processes

that they determined to be carcinogenic. OSHA

has issued health standards for 21 of the 71 chemicals or processes. Two of these OSHA standards

were struck down by the courts. Thus, 19 of the

71 NIOSH recommendations on carcinogens have

actually been addressed by OSHA regulations. Of

the 50 chemicals or processes that are not the subjects of a final OSHA standard based on carcinogenicity, many are still regulated under the

1971 startup standards. OSHA has proposed regulations for four, but is actively working on a final standard for only one. No OSHA proposals

have been issued for the remaining 46 chemicals

or processes.

OSHA has criticized the quality of early NIOSH

criteria documents, yet OSHA’s failure to respond

with standards highlights OSHA’s regulatory difficulties. Increasingly, OSHA’s regulatory agenda

is being set by outside groups, in the form of petitions, court orders, congressional directives, and

EPA referrals, including those on seven chemical

carcinogens that EPA formally or informally referred under TSCA. OSHA has proposed a standard for one of these referred substances.

MSHA

MSHA regulation covers coal mines and metal

and nonmetal mines. Regulation of toxic exposures in mines consists largely of reference to

the 1972 and 1973 recommendations of ACGIH,

depending on the type of mine. The ACGIH recommendations are updated annually, while

MSHA has changed few of its standards.

In the late 1970s, MSHA regulated asbestos exposures for surface mines (using the exposure limit

OSHA issued in 1972) and the chemicals OSHA

included in its “14-carcinogens standard. ” MSHA

has also proposed revised standards for underground exposure to radon daughters.

OSHA set a stricter standard for asbestos in

1986, but MSHA has not followed suit. Moreover, MSHA’s current asbestos standard does not

apply to exposures in underground coal mines.

The increased use of diesel engines in underground

coal mines has exposed workers to fumes. While

MSHA has standards for such exposures in metal

and nonmetal mines, these standards were not

based on carcinogenicity. MSHA is developing

a proposed standard for diesel exposures in coal

mines.

FDA Actions on Food and Color Additives

Since congressional enactment in 1958 of the

Delaney clause, which prohibits the use of food

additives determined to cause cancer, FDA has

identified over 60 relevant carcinogenic chemicals.

They include direct food additives, indirect food

additives (chemicals that might migrate from

packaging material or manufacturing processes

into foods or beverages), color additives, cosmetic

ingredients, contaminants or potential contaminants of food or color additives, and environmental or unavoidable contaminants of food.

The regulation of food additives received much

public attention when FDA banned cyclamates

and proposed to ban saccharin. FDA has actually banned seven direct food additives. Its proposed ban of saccharin was barred by congressional action.

The review of provisionally approved color additives, begun in 1962 under the Color Additive

Amendments of 1960, has been lengthy. It has

taken until now to obtain required toxicity data

and make regulatory decisions about many of the

substances on the list. FDA has banned a total

of 10 color additives, while a number of other

color additives were withdrawn from the market

by their sponsors who sometimes chose not to

conduct the FDA-required testing.

In the last few years FDA policy on regulating

food and color additives has also changed. Prior

to 1982, FDA banned several color additives because they were shown to be carcinogenic or contaminated with a carcinogen. Since 1982, FDA has

permanently listed several color additives even

though they contain known carcinogens. The new

policy states that, if a color additive itself does

not cause cancer in humans or animals, but a contaminant of the additive does, FDA will regulate

this color additive based on the general safety provisions of the act. Under this policy, the carcinogenic impurities are not considered to trigger the

requirements of the Delaney clause. FDA will estimate potential risk using quantitative risk assess-
11

ment techniques and if the risk of the impurities

is estimated to be low, FDA will permit the use

of the color additive.

In 1985 and 1986, FDA took action to allow

use of food and color additives that were themselves carcinogenic, basing its action on quantitative risk assessment. In 1985, FDA proposed to

allow the continued use of methylene chloride for

decaffeinating coffee by limiting the allowable residue, rather than to ban the chemical’s use entirely. Several color additives were identified by

FDA as carcinogenic in 1982 and 1983 based on

the results of animal bioassays. After performing

risk assessment calculations, FDA announced in

1986 that it was permanently listing these additives because their estimated carcinogenic risks

were low. FDA believes such actions are legally

permissible under the interpretation that the Food,

Drug, and Cosmetic Act allows FDA to ignore

de minimis risks, despite the seemingly absolute

language of the Delaney clause. In February 1987,

FDA argued further that because the estimated

risk in humans was low, the color additives in

question would not be considered, for purposes

of the Delaney clause, to be animal carcinogens

either.

Indirect food additives are generally packaging material—various plastics and adhesives used

to hold foods and liquids—and materials that contaminate foods in the manufacturing process. FDA

has banned two indirect food additives. Other indirect additives containing carcinogenic impurities have been regulated by prescribing conditions

for “safe use. ”

In the mid-1970s, FDA prohibited the use of

bottles made from polymers of acrylonitrile and

vinyl chloride, because these chemicals might

leach into liquids. FDA’s position was rejected by

the courts. In the 1980s, FDA issued a rule to allow acrylonitrile copolymer bottles and proposed

to allow polyvinyl chloride bottles, arguing that

new manufacturing technology can ensure minimal leaching from these bottles.

FDA can set regulatory tolerances or action

levels for environmental or unavoidable contaminants. It has set tolerances for PCB contamination of fish and action levels for aflatoxins,

dimethylnitrosamines (in malt beverages), and Nnitrosamines (in baby bottle nipples).

FDA Actions on Animal Drugs

FDA has identified 14 chemicals associated with

animal drugs that might leave carcinogenic

residues in animal tissues. Such residues had been

subject to the Delaney clause, but in 1962 Congress amended the Food, Drug, and Cosmetics Act

to permit the use of carcinogenic drugs in animals,

providing carcinogenic residues cannot be detected in meat or milk using FDA-approved methods. FDA has banned diethylstilbestrol (DES)

from use in animals and has required residue

studies on six other substances. FDA has proposed

to withdraw approval for seven. One animal drug

was withdrawn by the sponsor and there is no

reported action for several others. As mentioned

above, FDA has been working for 14 years on

regulatory guidelines specifying the SOM for determining the presence of harmful animal drug

residues.

FDA Actions on Human Drugs

In regulating carcinogens in human drugs, FDA

has issued rules on six substances or groups of substances. Two were removed from the market, one

was voluntarily recalled, and cautionary labeling

was required on three. When a drug is determined

to be carcinogenic, the drug’s labeling for physicians is usually updated informally. Many, but

not all, carcinogenic drugs on the market are, in

fact, anticancer drugs. Treatment in these cases

involves balancing the risk of future cancer against

the benefit of treating a diagnosed cancer today.

CPSC

Since its creation in 1970, CPSC has evaluated

and attempted to regulate or begun to regulate

eight chemicals (or groups of chemicals) for carcinogenicity. CPSC regulations have often been

overruled by the courts. although in the case of

Tris-treated children’s pajamas, CPSC developed

an alternative strategy to remove the product

from the market. In 1981, CPSC issued a rule regulating hazardous urea-formaldehyde foam insulation (UFFI), a rule that was also struck down

by the courts.
12

In other cases, use of chemicals in consumer

products stopped, even though regulation was not

final or had been overturned in court. In some

cases, CPSC has been able to negotiate voluntary

actions by manufacturers, such as the 1979 voluntary recall of hairdryers containing asbestos

shields.

EPA Actions Under the Clean Air Act

Since the 1970 enactment of the Clean Air Act,

EPA has, often under legal pressure, listed seven

carcinogens and issued hazardous air pollutant

emission standards on six, although one of these

actions was based on noncarcinogenic toxicity.

Although the Clean Air Act provides EPA one

year to issue regulations after a substance is listed,

this deadline was met only in the case of vinyl

chloride. EPA has taken an average of almost 4%

years from the date of listing to final action for

the six carcinogens on which it has issued final

rules. During the time between the listing and regulation of benzene, one major industrial source

of benzene had changed its process and eliminated

release of the chemical.

EPA has created a new type of action in addition to listing: an “intent to list” decision. According to EPA, the intent to list a substance as a hazardous pollutant does not legally bind the agency

as does a listing decision. EPA has indicated the

intent to list for 10 substances, but none as yet

has been listed and therefore none regulated.

EPA Actions Under the Clean Water Act

Important amendments to the Clean Water Act

were enacted in 1972, 1977, 1981, and 1987. From

1972 to 1975, EPA issued toxic effluent standards

for six categories of pollutants, under court order. In a consent decree, EPA agreed to regulate

toxic pollutants by industry and by specifying the

technology to be used. EPA agreed to issue effluent limitations for 65 categories of toxic substances, including 29 judged to be carcinogenic

according to the water quality criteria documents

that were also developed under this decree.

EPA has focused on 126 chemicals within these

65 classes of pollutants, but not all of these chemicals are regulated for every industry. In addition,

EPA has not established effluent limitations for

toxic pollutants from the organic chemicals industry, and current regulation of the pesticides industry does not limit the discharges of most toxic

pollutants in that industry. EPA had issued new

regulations for the pesticides industry, but they

were challenged in court and are now being reconsidered by EPA. Again, this regulatory activity

has taken considerable time (from the 1976 consent decree until today), has involved the courts

on a number of occasions, and is not yet finished.

Further, while the list of 126 chemicals was chosen based on known toxicity and probable presence in water, and represented the best efforts of

the participants at the time, more recent data reveal that many of the chemicals most commonly

found in industrial discharges are not on this list.

EPA has also prepared nonbinding water quality criteria documents for States to use in developing water quality standards and requirements

for specific discharge permits. However, only 7

of the 29 water quality criteria set for carcinogens

have been adopted by one or more States. For

only one of these substances (arsenic) have more

than one-fourth of the States issued a water quality standard, although in some States that have

not taken legislative action, individual discharge

permits impose limitations based on the water

quality criteria.

EPA Actions Under the Safe

Drinking Water Act

In 1975, EPA issued the “interim” drinking

water standards still used today for several inorganic and organic chemicals and for microbial

contaminants. These standards were based on the

1962 recommendations of the U.S. Public Health

Service for noncarcinogenic toxicities. EPA also

issued regulations for radionuclides in 1976 and

for total trihalomethanes in 1979, two groups of

substances presenting carcinogenic hazards.

Following the congressionally mandated reports

on drinking water by the National Academy of

Sciences (the first of six volumes was published in

1977), EPA was required to publish proposed recommended maximum contaminant levels (RMCLs)

and then to issue maximum contaminant levels

(MCLs) for particular chemicals found in drink-
13

.

ing water. The MCLs are to be set as close to the

RMCLs as is feasible. After considering a 1978

proposed regulation to set generic standards for

treating surface water supplies, EPA decided to

continue focusing on individual substances.

In 1982 and 1983, EPA published two Advanced

Notices of Proposed Rule-making (ANPRMs) listing 83 chemicals of concern. In 1983 and 1985,

it proposed RMCLs for inorganic substances,

volatile organic compounds, and synthetic organic

compounds. EPA issued final RMCLs for eight

volatile organic compounds in November 1985.

It has not yet issued final RMCLs for the inorganic substances and the synthetic organic compounds, and has not proposed RMCLs for radionuclides. To date, EPA has issued final MCLs for

nine chemicals, five of which are judged to have

sufficient evidence for carcinogenicity, and one

to have limited evidence.

Congress was concerned that drinking water

standards were not being set quickly enough, so

in the 1986 reauthorization of the act, it set deadlines for EPA to regulate the 83 chemicals that had

been identified as candidates for regulation in 1982

and 1983. These 83 substances include 51 in the

process of being regulated. In addition, 52 health

advisories have been issued by EPA. Many of

these provide information on potential carcinogens in drinking water.

EPA Actions Under FIFRA

To prevent unreasonable adverse effects on

health and the environment, FIFRA authorizes

EPA to screen pesticides before they enter the market and to regulate through reregistration the pesticides that were already on the market in 1972.

In both cases, EPA may require manufacturers to

conduct toxicity tests, including long-term bioassays for carcinogenicity.

FIFRA was substantially rewritten in 1972. At

that time there were about 50,000 pesticide products and 600 active ingredients previously registered by the Federal Government that needed

reregistration under the new law. The reregistration process has taken longer than originally anticipated. It was to have been completed by 1976,

but in 1975 Congress extended the deadline to

1977, and in 1978 Congress dropped the deadline

completely because of the large number of substances not yet reregistered. This task will OCCUPY

EPA for many years.

For a number of active ingredients subject to

reregistration, EPA has lacked sufficient information to judge their carcinogenic effects. EPA is taking steps to obtain this information. Still, as of

March 31, 1986, it had identified at least 81 carcinogenic active pesticide ingredients. Of these,

18 have been canceled or restricted, Daminozide

(Alar) is still undergoing review, and 15 have been

voluntarily canceled. However, cancellations

often cover only some uses. Other uses of the pesticide continue, although EPA may set additional

requirements, for example, requiring workers to

wear protective clothing. Special Reviews (SRs)

for the substances EPA canceled or restricted required from 13 to 88 months, taking an average

of about 44 months.

Another 18 chemicals have also been subjects

of SRs. The SRs have been completed for 10 carcinogens, and these chemicals have not been canceled based on EPA judgments weighing risks and

benefits. For the remaining 8 chemicals, SRs are

not yet complete. Finally, EPA has identified 29

carcinogens, but has not started SR or cancellation proceedings for any of these.

Thus, EPA has identified 47 carcinogenic active pesticide ingredients that have not been canceled. For 13 of these EPA has determined that

low exposure, low risk, or the weight of evidence

for carcinogenicity suggest no action need be

taken.

In addition to considering active ingredients,

EPA has indicated that about 55 inert ingredients

are of “high concern, ” with 28 of these showing

carcinogenic effects. In 1987, EPA announced for

the first time that it was taking steps to address

some of the hazards of these ingredients.

EPA Actions Under TSCA

EPA actions under TSCA cover both new and

existing chemicals. For new chemicals, the principal focus is the premanufacture review process.

If after review of the manufacturer’s premanufacture notice (PMN), EPA decides that there is cause

for concern, it can request or require that addi-
14

tional toxicity testing be done, that certain controls be used when working with the chemical,

and that the manufacturer notify EPA before beginning a significant new use of the chemical.

From mid-1979, when the PMN program began, until September 1986, EPA received 7,356

valid PMNs. Of these, 80 percent or 5,671 required no further action, according to EPA. Of

the remaining chemicals, 523 were subject to some

kind of action; an unknown number of these

raised concerns about carcinogenicity. About half

the time, EPA attention led to the manufacturer’s

informally and voluntarily agreeing to testing,

control actions, or withdrawal of the PMN. For

the remaining cases, EPA took more formal action, although often with the manufacturer’s

consent.

The lack of information in the PMNs is a potential problem. In 1983, OTA found that about

half the submitted PMNs reported no toxicity information and “only 17 percent of PMNs have

any test information about the likelihood of the

substance’s causing cancer, birth defects or mutations. ” Because many PMNs do not provide any

toxicity test data, EPA uses information on chemical structure-activity relationships to attempt to

predict the hazards that a substance may present.

For existing chemicals, EPA can require toxicity and environmental effects testing, designate

the chemical for accelerated review, or require

manufacturers to report on production and uses,

provide EPA with any studies they have conducted, or report significant new uses. EPA can

also issue regulations restricting or banning the

production of a chemical or limiting its uses.

TSCA established an Interagency Testing Committee (ITC) to make recommendations on needed

testing for toxicity and environmental effects. In

the early years of the program, EPA’s responses

to the ITC recommendations provoked concern,

both because of EPA delays in deciding whether

to test and because of the particular administrative arrangements chosen for obtaining test data.

In addition to the ITC recommendations, EPA

could select other chemicals for testing. So far,

this has not occurred often, although this may be

changing.

A rule issued under section 8(a) of TSCA requires manufacturers to provide information

about the production and uses of a chemical,

while a rule adopted under section 8(d) requires

that manufacturers submit to EPA unpublished

health and safety studies. EPA has issued 8(a) and

8(d) rules for all the substances recommended by

ITC, but until recently for few additional chemicals. EPA has recently received data from manufacturers as part of its effort to update its inventory on all chemicals in commerce.

Sufficient toxicity information is available on

some existing chemicals to show they are carcinogenic. For these chemicals, the issues are determining whether the risks of cancer are “unreasonable” and what actions may be needed to

reduce or eliminate such risks. EPA’s Office of

Toxic Substances, which is in charge of the TSCA

program, has identified 38 chemicals or chemical classes as carcinogenic and has prepared risk

assessments for 21 of these.

But beyond the development of risk assessments

and the gathering of other information, regulatory

actions on existing chemicals have been limited.

Four chemicals have been designated for an accelerated review under section 4(f) (4,4’ -methylenedianiline, 1,3-butadiene, formaldehyde, methylene chloride). Consideration of the regulation

of occupational exposures to these chemicals has

been referred formally or informally to OSHA

since TSCA provides for referrals if EPA believes

another agency may be able to address a hazard.

Under TSCA authority, EPA began proposing

Significant New Use Rules (SNURs) for existing

chemicals considered to be carcinogenic. However, actions on carcinogens began in 1984, nearly

7 years after TSCA’s enactment. For carcinogenic

chemicals, EPA has now proposed six SNURs on

eight existing chemicals and has issued four.

Section 6 of TSCA provides wide-ranging authority to limit production and uses of chemicals,

including the authority to ban a substance. EPA

has proposed section 6 action on PCBs, asbestos,

chlorofluorocarbons, and metalworking fluids.

PCBS were banned by Congress in TSCA itself;

EPA regulations cover implementing that ban and

arranging for disposal of PCBs. EPA has also

banned propellant uses of chlorofluorocarbons,
15

but it has not yet taken action on the most important uses of this group of chemicals, which are

used in refrigeration and air-conditioning. Finally,

EPA has issued rules on identification of asbestos

in schools and proposed rules to require removal

in certain cases. EPA has also regulated asbestos

exposures for certain workers not covered by the

OSHA asbestos standard, although it has not

taken final action on a major proposal to limit

and eventually ban asbestos use. The proposal on

metalworking fluids is also not yet final.

EPA Actions Under RCRA

RCRA regulates the generators, transporters,

storers, and disposers of hazardous wastes. EPA’s

lists of hazardous wastes cover 361 commercial

chemicals and 85 industrial waste processes. When

possible, EPA has emphasized waste streams from

commercial processes rather than specific hazardous substances, to relieve waste generators of testing burdens and uncertainties in “relating a waste

containing many substances to a list of specific

substances. ” EPA has also issued a list of toxic

chemicals as Appendix VIII of its RCRA standards. Wastes containing chemicals on this list may

be deemed hazardous wastes.

EPA has made limited changes in its list of

RCRA hazardous wastes. For example, since 1980

EPA has added five wastes to the RCRA list. In

the 1984 RCRA amendments Congress employed

“hammers’’ -congressionally enacted prohibitions

against disposal of certain groups of chemicals unless EPA has acted to specify treatment techniques

for those wastes. In addition, Congress mandated

that EPA review, over a 3-year period, the entire

RCRA list of hazardous wastes.

EPA Actions Under CERCLA

Commonly known as Superfund, CERCLA was

enacted in 1980. CERCLA requires EPA to identify reportable quantities for hazardous substances

and set requirements for notification of environmental releases.

Congress specifically included in the definition

of hazardous substances those chemicals already

regulated under several environmental statutes.

In addition, Congress set reportable quantities for

these substances at 1 pound (except for reportable quantities specified under the Clean Water

Act) until EPA could set more appropriate reportable quantities. In May 1983, EPA published its

initial list of hazardous substances. Since 1983,

19 substances have been added to the CERCLA

list yielding a total of 717 substances. Most of the

regulatory activity on the CERCLA list has been

in modifying the reportable quantities. In 1987,

EPA proposed modified reportable quantities for

CERCLA carcinogens. Of the CERCLA hazardous substances, 191 have been identified by EPA

as “potential carcinogens” or as substances “having carcinogenic potential. ”

EPA’s Carcinogen Assessment Group (CAG)

As mentioned above, CAG was established in

1976 to centralize the conduct of carcinogen risk

assessments at EPA. Major CAG assessments are

thorough reviews of the carcinogenic risks of particular chemicals, including both qualitative

evaluation of the weight of evidence for carcinogenicity and quantitative dose-response estimates.

To date, CAG has prepared full assessments on

57 chemicals.

Office of Management and Budget (OMB)

Although not a regulatory agency, OMB has

become an important actor in developing Federal

regulations through their review of proposed regulations under Executive order 12291 and the

Paperwork Reduction Act. This review has led

to delays in proposing and issuing standards on

carcinogens. OMB has also publicly questioned

some of the regulatory agencies’ assumptions in

conducting risk assessments. The methods OMB

used in commenting on a proposed OSHA formaldehyde standard ran counter to some of the

assumptions typically used by the regulatory

agencies and incorporated in agency policies on

identifying and assessing carcinogens.

Type of Evidence: Human or

Animal Data

Agencies use the hazard data available at the

time of their action, most generally, data from

human or animal studies. OTA has attempted to

characterize the evidence that agencies have used

in regulating carcinogens.
16

FDA has relied mostly on animal evidence in

evaluating food additives, color additives, human

drugs, and animal drugs.

CPSC has used both human and animal evidence, although in its action on Tris and attempted regulation of formaldehyde, it relied

upon animal evidence only.

Of the 57 chemicals covered by CAG health

assessments, 40 have been assessed based on

“sufficient” animal evidence. Nine more were supported by sufficient human evidence and all but

one of these were also supported by sufficient animal evidence. EPA judged the remaining 8 chemicals to have inadequate human evidence and

limited animal evidence.

Most cancellations and restrictions of pesticides

have been based on the results of carcinogenicity

tests in at least two animal species. Nearly all

TSCA hazard identifications and risk assessments

are based on animal data.

There is some evidence of the carcinogenicity

of the 35 chemicals proposed for regulation under the Safe Drinking Water Act, but EPA believes

that the evidence for the carcinogenicity of 8 of

these in drinking water has not been established

and thus is basing RMCLs for these chemicals on

noncarcinogenic effects. EPA’s classification of the

other 27 drinking water contaminants as carcinogens relied mostly on animal evidence.

The original RCRA list of hazardous wastes and

CERCLA list of hazardous waste reportable quantities were developed largely without specific concern for carcinogenicity, although the original regulations on which these lists were based may have

had this concern. Recently proposed adjustments

in the CERCLA list of reportable quantities classify 191 chemicals as potential carcinogens: 14

based on sufficient human evidence, 110 on sufficient animal evidence, and 20 on limited animal

evidence. Most (40) of the remaining chemicals

were classified based on a parent element (e.g.,

inorganic compounds of arsenic were classified

based on the carcinogenicity of arsenic), although

for 7 chemicals EPA had no evidence of carcinogenicity.

OSHA and EPA’s Clean Air Program have

based regulation on human data most of the time,

though there are indications this may be changing.

Of OSHA’s eight regulations on individual carcinogens, seven were based on at least some evidence of human carcinogenicity. The other carcinogen, 1,2-dibromo-3-chloropropane (DBCP),

was regulated primarily because it caused infertility in men. The evidence of its carcinogenicity

consists of animal data. Regulation of three carcinogens under the “14-carcinogen standard” was

based on human evidence, that of nine on animal

evidence. The remaining two substances were regulated because of their chemical relationship to

other carcinogens. Most OSHA regulations of carcinogens based only on animal evidence occurred

with the regulation of the 14 carcinogens in 1974.

Standards since then have been based mostly on

human data, although for OSHA’s 1984 regulation of ethylene oxide the primary evidence for

its carcinogenicity is animal data. The primary

evidence for several chemicals now being considered for regulation, including formaldehyde and

methylene chloride, is animal evidence.

For the five substances regulated primarily as

carcinogens under the Clean Air Act, EPA has relied on human evidence of carcinogenicity. EPA’s

intent-to-list decisions for eight of ten substances

have relied on animal bioassays for evidence of

carcinogenicity; the other two substances show

both animal and human evidence of carcinogenicity.

The National Toxicology Program

(NTP)

Since 1961, the Federal Government has been

developing a testing program for determining the

carcinogenicity of chemicals, first at NCI, and

since 1978, at NTP. The program encompasses

long-term animal studies and other tests to determine carcinogenic activity. NTP is probably the

largest such testing program in the world, and is

thus important in advancing knowledge of carcinogenic chemicals.
17

Early testing at NCI focused primarily on understanding the etiology and biological mechanisms of cancer. In the late 1960s, the Federal

Government expanded carcinogenicity testing.

Today, NTP bioassays and other tests provide important information for developing risk assessments and issuing regulations.

NTP was created to coordinate the toxicity testing of the then Department of Health, Education,

and Welfare and to provide a mechanism for regulatory agencies (and others) to request bioassays

on chemicals of regulatory interest. The NTP budget consists of contributions from several different agencies in the Department of Health and

Human Services (FDA/National Center for Toxicological Research (NCTR), CDC/NIOSH, and

the National Institute of Environmental Health

Sciences (NIEHS)), although the lion’s share of

funds derive from NIEHS. The Director of NIEHS

is also the Director of NTP. Activities of the contributing agencies are coordinated by the NTP

Steering Committee, which consists of the heads

of these agencies and the NTP Director. Formal

authority to approve and monitor the general plan

of NTP activities is vested in an Executive Committee that consists of the heads of the four major health and environmental regulatory agencies

(CPSC, EPA, FDA, and OSHA), the heads of four

research agencies (National Institutes of Health

(NIH), NCI, NIEHS, and NIOSH) and the Assistant Secretary for Health of the Department of

Health and Human Services (DHHS). This structure allows both the regulatory agencies and research agencies a voice in planning and operating NTP.

The nomination of chemicals for NTP testing

is invited from any source, including the regulatory and research agencies. NTP’s established procedures to evaluate nominations include review

by the interagency Chemical Evaluation Committee, solicitation of public comments, review by

NTP’s Board of Scientific Counselors, and final

decision by the NTP Executive Committee.

After selection, a protocol is prepared and testing begins. Testing consists of various preliminary

studies, a long-term dosing regimen (which by itself takes 2 years), sacrifice, and pathologic examination, including microscope studies of tissues

and tumor diagnoses. NTP has established procedures for ensuring the quality of these diagnoses, which are crucial to determining the final bioassay results. The resulting data are analyzed and

the draft technical report is submitted to a peer

review committee. Peer reviewers have the training and experience appropriate to judge the quality of the bioassay and to interpret bioassay results. NTP has chosen to include on its peer review

committees people of different perspectives, including academics and representatives of industry, environmental organizations, and labor

unions.

The number of chemicals tested depends primarily on the resources available. The NTP budget increased approximately 40 percent between

1979 and 1981. From fiscal year 1981 to 1987 the

total NTP budget rose from $70.5 to $77.9 million, which, after adjustment for inflation, represents a small decline. Budget reductions necessitated by the Gramm-Rudman-Hollings Act have

affected NTP. Recently, NCTR discontinued longterm NTP animal tests on one antihistamine and

continued two other tests only because NIEHS

agreed to pay 75 percent of the costs to complete

the 2-year exposure phase. NTP has now agreed

to fund completion of these two studies. Given

current resources, more chemicals are nominated

than can be tested.

The entire process—nomination, selection, preliminary testing, chronic testing, necropsy, data

analysis, review, and publication—is a long one.

OTA examined the process for a group of chemicals reviewed by NTP’s Chemical Evaluation

Committee in fiscal year 1981 and 1982. None of

these chemicals has passed through the entire testing process. Of the 30 chemicals approved for testing in those 2 years, 4 have reached the stage of

chronic testing.

The time from nomination to selection is more

than 2 years for most chemicals. Some shortening of this period should be possible. But much

of the remaining time required (between selection

and beginning chronic exposures) is difficult to
18

shorten because it is used to develop information

important for the design, conduct, and interpretation of the bioassay.

The nomination process raises at least two issues. First, nominations and selections are important because they may set the regulatory agenda

for the following decade. Today, several agencies

are working on regulations for such chemicals as

methylene chloride, 1,3-butadiene, 4,4’-methylene

dianiline, and benzene, which NTP tests showed

to be carcinogenic. These test results and the resulting regulatory action proceed in part from

selection decisions of a number of years ago.

Second, NTP’s recent decisions on testing the

benzodiazepines (which include Valium and

Librium) raise the issue of who should pay for carcinogenicity testing—government manufacturers,

drug sponsors, pesticide registrants, or others.

There are advantages to testing through common

protocols and in the Federal Government’s program. There is also reason to argue that the manufacturers and sponsors of chemicals have a

responsibility to pay for the toxicity tests of their

products.

Regulatory Responses to NCI/NTP

Test Results and the Annual Report

NCI/NTP Bioassay Results

As of June 1987, the NCI/NTP bioassay program has completed testing of 308 chemicals in

a total of 327 studies. Chemicals are typically

tested in both sexes of rats and mice, for a total

of four “experiments. ” At the end of the study,

the results of each experiment are classified as

clear evidence, some evidence, equivocal evidence, or no evidence for carcinogenicity, or as

an inadequate test.

OTA has analyzed the regulatory uses of the

NCI and NTP test results subject to peer review

and audit approval by September 1986. These results represent 284 chemicals studied in 295 tests.

For the analysis, “clear evidence” and “some evidence” for carcinogenicity were grouped as “positive” results. The chemicals tested were grouped

based on the number of the four experiments for

each that showed positive results. Of the 284

chemicals, 36 yielded four positive results, 25

three positives, 51 two positives, and 32 one positive result, for a total of 144 chemicals testing positive in at least one experiment.

OTA did not incorporate any additional data

on the affected animal tumor sites, on whether

both high and low doses (or all three doses in a

three-dose experiment) produced a response, or

on chemicals’ estimated potencies. The grouping

of substances for this analysis is also based only

on the results of NCI/NTP testing. OTA has not

used the bioassay results of others or the results

of human epidemiologic studies.

Annual Report on Carcinogens

In 1978, Congress mandated that the DHHS

publish an annual report listing all known carcinogenic substances and substances reasonably

thought to be carcinogenic to which a significant

number of people in the United States are exposed.

Furthermore, the report is to describe regulatory

actions on these substances, and estimate how

much those actions have reduced risk. The legislation’s first sponsors thought this discussion

would help focus on chemical exposures that still

present risks, and thus on areas for regulatory

activity.

The substances discussed in the report are chosen by an interagency committee, including representatives of CPSC, EPA, FDA, NCI, NIEHS,

NIOSH, the National Library of Medicine, and

OSHA. The committee bases its decisions on the

previous Annual Report, lists of chemicals judged

to be supported by sufficient evidence for carcinogenicity by the International Agency for Research on Cancer (IARC), and animal testing results from NTP and other peer-reviewed studies.

They publish the list of possible additions for comments and then make their final selections, The

latest Annual Report, the fourth, lists a total of

148 substances, groups of substances, and exposures. For this analysis, OTA eliminated doublecounted chemicals in this list for a total of 145

chemicals.

OTA Analysis

OTA examined regulatory responses to three

groups of chemicals: all NCI/NTP-tested chemicals with at least one positive experiment, the
19

NCI/NTP chemicals with three or four positive

experiments, and the chemicals listed in the fourth

Annual Report on Carcinogens. While OTA analyzed the three separately, in fact there is some

overlap of the three lists. All the chemicals testing positive in three or four experiments of course

also tested positive in at least one experiment. In

addition, many of the chemicals with three or four

positive results have been listed in the Annual

Report.

OTA focused on the chemicals of potential regulatory interest for each agency or program: the

chemicals found in specific environmental media,

such as air or drinking water, occupational settings, consumer products, pesticides, food, and

drugs. Information on exposures is, unfortunately, often simply unavailable. Quantitative information is particularly difficult to obtain. So

OTA relied on information on estimated production levels, estimated number of workers exposed,

and qualitative data on the presence of particular chemicals in given situations. Even using this

information on regulatory jurisdictions, OTA

found apparent gaps in regulatory coverage. Figure 1-2 summarizes OTA’s analysis of agency actions and nonactions on chemicals in their jurisdictions.

The impact of these regulatory gaps on human

health depends on factors not analyzed by OTA,

including the extent and magnitude of exposures,

the potency of the chemicals, and other potentially synergistic or antagonistic exposures and

risk factors. Many agency analyses conducted to

develop information prior to regulation on information hazards, risks, control technologies, costs,

and other factors—have not been included in the

actions discussed here.

Regulation of Chemicals Tested by NCI/NTP

While a number of regulatory actions appear

to have been based directly on positive NCI/NTP

test results, there also appear to be substantial

gaps in regulatory activity. In the NCI/NTP bioassay program, 144 chemicals tested positive in

at least one experiment. Considering each agency

and program individually reveals that no agency

has regulated more than a third of the chemicals

with positive test results. More typically, an individual agency will have acted out of concern

for carcinogenicity on 5 to 30 of the 144 chemicals.

FDA has taken action on 17 of the 48 positive

NCI/NTP chemicals associated with food additives, color additives, or cosmetics. The balance

have been evaluated, but have not been subject

to further action. FDA has acted on 4 of the 5

positive NCI/NTP chemicals associated with animal drugs, and 6 of the 12 positive NCI/NTP

chemicals that are human drugs bear labeling that

warns of carcinogenicity. OSHA has set exposure

standards for 29 of the 53 positive NCI/NTP

chemicals that are of interest in the workplace,

although 27 of these 29 are regulated by standards based on concern for noncarcinogenic toxicity, which were adopted by OSHA in 1971.

NIOSH has provided OSHA with recommendations on 31 of the 62 positive NCI/NTP chemicals in its OTA-defined jurisdiction. Regulatory

action or voluntary exposure reductions have

occurred for 8 of the 14 positive NCI/NTP chemicals in CPSC’s jurisdiction. EPA has listed under the Clean Air Act 2 of 12 positive NCI/NTP

chemicals within the act’s jurisdiction. Water quality criteria have been prepared for 14 of the 27

positive NCI/NTP chemicals in the jurisdiction

of the Clean Water Act. Of the 14 positive

NCI/NTP chemicals in the jurisdiction of the Safe

Drinking Water Act, 12 have been addressed by

some regulatory attention, although for many of

these, the regulatory process is not yet finished.

EPA has developed information on 53 of the 144

positive NCI/NTP chemicals in the TSCA’s jurisdiction. For 5 of the 144 chemicals, EPA has issued SNURs, begun accelerated reviews, or taken

action under section 6 of the act. Under FIFRA,

there have been EPA-ordered or voluntary cancellations for 13 of the 22 positive NCI/NTP

chemicals used as active pesticide ingredients. Of

the 144 positive NCI/NTP chemicals, 41 have

been included in RCRA’s list of hazardous wastes

or its Appendix VIII list, while 47 of the 144

positive NCI/NTP chemicals are listed under

CERCLA. CAG has prepared health assessments

for 22 of the 144 positive NCI/NTP chemicals.

No actions have occurred for 43 of the 144 positive NCI/NTP chemicals.
20
21

Limiting attention to those chemicals with three

or four positive experiments reveals that agencies

and programs have each acted on 1 to 22 of the

61 NCI/NTP chemicals with these results. Chemicals with three or four positive experiments will

generate greater concern because in these cases

there are positive results from both rats and mice.

FDA has taken some regulatory action on 7 of

the 19 chemicals with three or four positive experiments associated with food or color additives

or cosmetics. The one animal drug with three or

four positive results has been revoked whiles of

the 6 chemicals with three or four positive experiments have been removed from human drugs or

have been labeled for carcinogenicity. OSHA has

regulated 16 of the 30 chemicals with three or four

positive experiments that are in its jurisdiction.

One of these standards is based on carcinogenicity. NIOSH has made recommendations on 13 of

the 39 chemicals in its jurisdiction with three or

four positive results. In CPSC’s jurisdiction, 4 of

7 chemicals have been subject to regulatory or

voluntary action. Under the Clean Air Act, EPA

has listed one of eight chemicals with three or four

positive results. Water quality criteria have been

issued for 7 of 10 chemicals in the Clean Water

Act jurisdiction, and some regulatory action has

occurred for 6 of the 7 chemicals under the jurisdiction of the Safe Drinking Water Act. Information has been developed under TSCA for 22 of

the 61 chemicals with three or four positive experiments and SNURs, accelerated reviews, and

section 6 actions have addressed 2 of the 61. EPAordered and voluntary cancellations have occurred for 5 of the 11 active pesticide ingredients

with three or four positive experiments. RCRA

lists include 22 of the 61 chemicals with three or

four positive experiments, and the CERCLA list

covers 22 of the 61. CAG assessments address 9

of the 61. No actions have addressed 23 of the

61 chemicals with three or four positive experiments.

Regulation of Chemicals Listed in

the Annual Report on Carcinogens

All the Annual Report chemicals have been addressed by at least one agency, although a large

number of these chemicals have not been acted

on by all the agencies and programs that might

have an interest in them. Except for chemicals on

the lists adopted under RCRA and CERCLA, no

agency has regulated as many as half the chemicals included in the Annual Report. Generally,

agencies have acted on 5 to 60 of these 145 Annual Report chemicals.

FDA has acted on 46 of the 52 Annual Report

chemicals in its jurisdiction for food and color additives and cosmetics, and on 2 of the 6 Annual

Report chemicals used as animal drugs. Of the 31

Annual Report chemicals with human drug uses,

26 have been removed from the market or have

carcinogenicity warning labels. OSHA has exposure standards for 52 of 110 Annual Report

chemicals in its jurisdiction; 17 of these standards

are based on carcinogenicity. All Annual Report

chemicals are covered by OSHA’s hazard communication standard. NIOSH has made recommendations on 59 of the 112 Annual Report chemicals in its jurisdiction. Voluntary and regulatory

actions have been taken on 18 of the 23 Annual

Report chemicals in CPSC’s jurisdiction. EPA listings under the Clean Air Act address 6 of 15 Annual Report chemicals in the act’s jurisdiction. For

48 of 65 Annual Report chemicals in the jurisdiction of the Clean Water Act, water quality criteria have been prepared. Interim standards under the Safe Drinking Water Act, and the current

RMCL/MCL process address 21 of 32 Annual Report chemicals within the act’s jurisdiction. EPA

has developed information on 28 of the 145 Annual Report chemicals in the TSCA jurisdiction

and issued SNURs, started accelerated reviews,

or section 6 actions on 6 of the 145. EPA-ordered

and voluntary cancellations have affected 12 of

the 24 Annual Report chemicals used as active ingredients in pesticides. The RCRA lists address

97, and the CERCLA lists 95 of the 145 Annual

Report chemicals. CAG assessments cover 78 of

the 145.

Comments on the OTA Analysis

In comments on a draft of this background paper, officials of Federal regulatory agencies emphasized their belief that they have acted appropriately in regulating the chemicals tested by

NCI/NTP and the chemicals in the Annual Report. They pointed out that statutes require they
22

assess the risks and benefits of using chemicals,

and the technical feasibility and costs of regulatory action. Because of these considerations, as

well as their judgments about the weight of evidence for carcinogenicity, in some cases they have

decided not to regulate substances. In other cases,

the chemicals are being considered as subjects of

regulatory action.

Future Improvements

Today the hope for a more complete understanding of cancer causation rests on research into

biochemical markers, pharmacokinetics, and molecular mechanisms. Nevertheless, science cannot

now answer all the questions that are raised in

this field. Even in the face of such uncertainty,

however, it is important to take action to protect public health.

Ever since the development of carcinogenicity

bioassays, there has been skepticism about the

reliability of animal results for estimating human

risk. The Federal agencies have usually assumed

the usefulness of animal test results. However, regulated industries have often disputed these results

in particular cases and express concern that society not impose unnecessary regulations. These disputes are not likely to go away.

To force regulatory action, Congress has legislated a variety of statutory mechanisms. The most

common of these have been statutory deadlines,

which have sometimes led to regulatory action,

but are also frequently missed by the agencies.

In the 1984 RCRA amendments, Congress included “hammers”-statutory provisions that go

into effect if EPA misses particular deadlines. Congress has also mandated requirements, such as

TSCA’S ban of PCBs, and agency adoption or

consideration of designated lists of chemicals. In

one case (that of saccharin regulation), Congress

prohibited an agency from acting. A final congressional mechanism is requiring agencies to consider or respond to recommendations of another

agency or organization. For example, OSHA must

consider the recommendations of NIOSH, EPA

must respond to nominations of chemicals by the

ITC, and, in the original Safe Drinking Water Act,

EPA was to respond to National Academy of Sciences recommendations.

In light of the regulatory gaps revealed by

OTA’s analysis of agency responses to positive

NCI/NTP bioassay results and the list of chemicals in the Annual Report on Carcinogens, Congress may wish to consider a statutory requirement mandating that agencies regulate these

chemicals or at least publicly respond to these

sources of information, even if, for various reasons, they choose not to regulate. On the other

hand, such a requirement might make developing the Annual Report or selecting chemicals for

NTP testing more difficult. In addition, regulatory action may not always be necessary and, if

taken, may impose costs on regulated industries.

Finally, in light of the importance exposures play

in determining the need for regulation, it might

be appropriate to develop additional information

on the extent of human exposures to these

chemicals.
Chapter 2

Policies for Testing, Assessing,

and Regulating Carcinogens
CONTENTS

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Types of Evidence . . . . . . . . . . . . . . . . . . . . 25

Risk Assessment and Risk

Management . . . . . . . . . . . . . . . . . . . . . . . 26

Qualitative and Quantitative Risk

Assessments . . . . . . . . . . . . . . . . . . . . . . . 27

Inference Guidelines and Policies . . . . . . . 27

Utility of Policies . . . . . . . . . . . . . . . . . . . . . 28

History of Agency Policies . . . . . . . . . . . . . . 29

The Food and Drug Administration . . . . 29

The Environmental Protection Agency . . 31

The Consumer Product Safety

Commission . . . . . . . . . . . . . . . . . . . . . . . 34

The Occupational Safety and

Health Administration . . . . . . . . . . . . . . 34

Other Agencies and Interagency

Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Guidelines for Conducting

Carcinogenicity Testing . . . . . . . . . . . . . 37

Required Carcinogenicity Testing . . . . . . . 37

Analysis of Test Designs . . . . . . . . . . . . . . 38

Analysis of Agency Carcinogen

Assessment Policies . . . . . . . . . . . . . . . . . 44

Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Qualitative Risk Assessment:

Hazard Identification . . . . . . . . . . . . . . . 45

Quantitative Risk Assessment:

Dose-Response Determination . . . . . . . . 52

Agency Policies on Dose-Response

Assessment . . . . . . . . . . . . . . . . . . . . . . . . 53

Agency Practice of Quantitative

Risk Assessment . . . . . . . . . . . . . . . . . . . . 58

Agency Policies on Human Exposure

Estimation . . . . . . . . . . . . . . . . . . . . . . . . . 60

Risk Characterization . . . . . . . . . . . . . . . . . 61

New Areas for Risk Assessment Policy. . 62

Classificationof Carcinogens . . . . . . . . . . 65

Agency Policies on Carcinogen Risk

Management . . . . . . . . . . . . . . . . . . . . . . . 71

Regulatory Prodecures . . . . . . . . . . . . . . . . 71

Regulatory and Research Priorities . . . . . 72

Page

Office of Management and Budget Policy

on Carcinogen Risk Assessments . . . . . 72

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Boxes

Box No. Page

2-A.

2-B.

2-c.

2-D.

2-E.

2-F.

2-G.

Development of “Cancer Principles”

at the Environmental Protection

Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

1987 Classification of Carcinogens by

the International Agency for Research

on Cancer . . . . . . . . . . . . . . . . . . . . . . . . 66

1986 Classification of carcinogens

by National Toxicology Levels of

Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . 68

1986 Classification of carcinogens

by the Environmental Protection

Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

1979 Classification of Carcinogens in

the EPA Airborne Carcinogen Policy. 70

1982 Classification of Carcinogens by

the Occupational Safety and Health

Administration . . . . . . . . . . . . . . . . . . . . 70

1978 Classification of Carcinogens

by the Consumer Product Safety

Commission. . . . . . . . . . . . . . . . . . . . . . . 70

Figures

Figure No. Page

2-1. A Stylized Dose-Response Curve and

Some Extrapolated Curves . . . . . . . . . . . 53

2-2. Possible Types of Dose-Response

Curves in the Low-Dose Region . . . . . 56

2-3. Possible Types of Relationships

Between Administered and Effective

Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Table

Table No. Page

2-1. Test Design Issues . . . . . . . . . . . . . . . . . . 40
Chapter 2

Policies for Testing, Assessing,

and Regulating Carcinogens

INTRODUCTION

Over the last dozen years, health, safety, and

environmental regulatory agencies have issued

guidelines and policies on how they intend to identify, evaluate, and regulate carcinogens. Some

guidelines and requirements address the design of

toxicity tests in animals. Other policies describe

the kinds of evidence, human or animal, that the

agencies will use to identify and evaluate carcinogens. In these policies, agencies have given considerable attention to methods for predicting the

nature and extent of possible human health risks

based on human and animal data.

Some of the important issues in assessing potentially carcinogenic chemicals turn on the interpretation of test data, others on the use of assumptions (or “inference options”). These assumptions

are derived from theories about cancer causation

and decisions about appropriate public policy.

OTA has identified four important kinds of assumptions:

1.

2.

3.

4.

assumptions used when data are not available in a particular case;

assumptions potentially testable, but not yet

tested; 1

assumptions that probably cannot be tested

because of experimental limitations; and

assumptions that cannot be tested because

of ethical considerations.

The lack of data and use of risk assessment assumptions, especially in conjunction with underlying political disputes about the desirability of

government regulation, make this area of research

the subject of lively debates.

This chapter will describe and compare the Federal agency policies that attempt to resolve cer-

‘One important area of research is testing such assumptions and

developing new experimental methods. Such work is taking place

at the National Institute of Environmental Health Sciences and National Center for Toxicological Research.

tain issues in identifying carcinogens and assessing human risks. These policies include the

guidelines on the design of animal bioassays for

carcinogenicity, the guidelines governing the regulatory use of human epidemiologic data, animal

toxicology tests and other information on toxicity, and the procedures for combining all this information in risk assessments.

The study of carcinogenesis is advancing rapidly. In this chapter, OTA has not attempted to

summarize current scientific understanding, but

only to describe and compare Federal agency policies on testing, assessing, and regulating carcinogenic chemicals. In addition to following procedures described in this chapter, agencies must also,

prior to regulatory action, meet certain other statutory requirements. Depending on the statute,

these may involve determining that the estimated

risk is unreasonable or significant, that exposure

reduction is technologically achievable, that the

costs of control are economically achievable or

proportionate to the benefits anticipated, and that

the relevant statute authorizes regulatory activity for that hazard. These additional steps are not

discussed in this chapter.

Types of Evidence

Four kinds of evidence may be used for qualitatively identifying carcinogens: epidemiologic

studies, long-term animal bioassays, short-term

tests, and structure-activity relationships. (See ref.

217 for a more detailed discussion of methods for

identifying carcinogens. )

Epidemiologic studies collect information about

human exposures and diseases. Reports of individual cases or clusters of cases are very often used

to generate hypotheses for later study. In fact,

many of the chemicals now determined to be human carcinogens were first identified in case

reports by astute physicians. Larger epidemiologic

studies are divided into descriptive, or correla25
26

tional, studies and analytic studies. Descriptive

epidemiologic studies correlate risk factors (including exposures) and diseases or causes of death

in populations. They are useful in generating hypotheses for further study and in providing clues

about potential hazards. Analytic epidemiologic

studies use comparison populations. In cohort

studies, the comparison is made between a group

exposed to the agent of interest and a group that

is not exposed. For case-control studies, the comparison is made between people with a given disease and those without the disease.

Long-term animal bioassays are laboratory

studies in which animals are exposed to a suspected hazard (for about 2 years in the case of

rodents). The animals are examined for the presence of tumors and other signs of disease throughout the study. At the end of the study, the surviving animals are sacrificed. Tissues from these

animals and from those that died during the study

are given gross and microscopic examinations and

tumors are diagnosed. The incidence of tumors

in exposed and control groups is then compared.

Short-term tests examine genetic changes in laboratory cultures of cells, or in humans or other

animals, or in lower organisms. These tests take

relatively little time to perform. Short-term tests

can be completed in days, weeks, or a few

months, rather than requiring the several years

needed to complete a bioassay in rodents.

Structure-activity relationships (SARs) in this

context refer to associations between chemical

structures and carcinogenicity. In a sense, judgments about them are “paper chemistry, ” because

predictions are made about the carcinogenicity of

substances based on previously observed associations between structure and toxicity, but without

additional toxicity testing. The predictive value

of using SARs is highest for chemicals within a

class of closely related chemicals for which extensive carcinogenicity testing has already been conducted. Predictions based on SARs are less certain for classes of chemicals less extensively tested.

Many of the Federal carcinogen guidelines discuss the different roles to be played by the different kinds of evidence, as is discussed below. All

of these policies value positive epidemiologic

studies as the most conclusive evidence for human carcinogenicity, they generally presume that

substances carcinogenic for animals in long-term

bioassays should be treated as carcinogenic for

humans, and they treat short-term test results as

supporting information.

In practice, regulatory activity maybe initiated

based on positive human or long-term animal

data. In most cases, if the only evidence consists

of short-term test results, agencies will not initiate regulatory action to reduce exposures, although such test results might be the basis for requiring further animal testing. SARs are used

mostly when no other data are available, for example, to identify new chemicals for which further testing is warranted prior to large-scale manufacture.

The relative ranking of these types of evidence

is often an academic issue because for many types

of chemicals, there are often few toxicity data of

any sort, whether from human epidemiology,

long-term animal bioassays, or short-term tests

(138). In these situations, Federal agencies may

be hampered in their efforts to protect public

health.

Risk Assessment and

Risk Management

It is common now to distinguish between risk

assessment and risk management (111). This language was adopted in the report of a Committee

on the Institutional Means for the Assessment of

Risk to Public Health convened by the National

Research Council of the National Academy of Sciences (NAS) (137). This committee described risk

assessment as the process of characterizing the adverse health effects of human exposures to environmental hazards. Risk assessment relies on

information from epidemiologic, clinical, toxicologic, and environmental research. Risk management, on the other hand, is the process of evaluating and choosing among regulatory options,

based on information on economic, social, political, and engineering factors, as well as information on risk.

Some of the agency policies described below

also outlined distinctions between risk assessment

and risk management, predating the NAS report.
2 7

The Environmental Protection Agency (EPA)

(1976) (293) describes two decisions: whether a

substance poses a cancer risk and what regulatory action, if any, should be taken to reduce risk.

The National Cancer Advisory Board (NCAB)

(1977) (348), the oldest of the policy documents

considered here in detail, argues that scientists

play a major role in evaluating benefits and risks

by providing and interpreting data, but “the final decision . . . must be made by society at large

through informed governmental regulatory and

legislative groups.” Thus, the division, real or perceived, between “scientific data and interpretation” and “political decisions” has been noted for

some time.

Risk assessment determines the qualitative nature of the risk posed by particular exposures to

chemical or physical agents and quantifies the

dimensions of that risk. The term “risk” has been

used in many ways. OTA uses “risk” to mean the

combined effects of the intrinsic hazard presented

by the agent in question and the degree of exposure. Thus, an inherently very toxic agent may

pose little risk when exposure levels are very low.

Conversely, an agent of low intrinsic toxicity may

be an important public health problem because

a large number of people are exposed at fairly high

levels.

Qualitative and Quantitative

Risk Assessments

One distinction, frequently made in discussing

policies on carcinogen regulation, is between the

qualitative determination of a hazard and the

quantitative evaluation of risk. The qualitative

determination is a “yes” or “no” answer to the

question: Does substance X cause cancer? These

decisions may be difficult and may even include

some quantitative analysis. For example, statistical techniques are used to determine whether an

exposed group of people or animals have a significantly higher than expected incidence of

tumors. In addition, qualitative determination depends on some interpretation, such as views on

whether animal carcinogens are presumed to be

human carcinogens, or whether benign tumors in

animals indicate a hazard for humans.

Quantitative risk assessment starts with the

qualitative determination that a substance does

cause cancer and then goes on to ask: To what

extent does exposure to a particular agent cause

tumors? The answer involves four separate analytic exercises: developing a mathematical description of the dose-response relationship, extrapolating from animal data to human effects, developing

information on human exposure levels, and using

all this information to estimate individual risks

and the number of expected cases in the human

population.

Instead of “qualitative” and “quantitative” risk

assessment, the NAS Committee on Risk Assessment used the terms hazard identification, doseresponse assessment, exposure assessment, and

risk characterization (137). These terms more

clearly describe the separate analytic steps in a

risk assessment, although the older terms will also

be used in this background paper.

Hazard identification determines whether exposure to an agent increases the incidence of an

adverse condition, for example, cancer in test animals. Dose-response assessment describes the relationship between the level of exposure or the dose

and the incidence of disease. The two most important aspects of this step are extrapolating from

information on incidence at high doses to predict

incidence at lower doses and, in the case of risk

assessments based on animal data, converting animal doses into equivalent human doses. Exposure

assessment estimates the frequency, duration, and

intensity of human exposures to the agent in question. Finally, risk characterization uses information from both dose-response and exposure assessments to estimate the expected incidence of the

adverse health effect.

Inference Guidelines and Policies

All the steps described above involve uncertainties, some owing to the lack of data on particular agents, some to lack of knowledge concerning the causes and mechanisms of toxicity. Where

the science is uncertain, inferences must be made.

The NAS Committee used the term “components”

to refer to the various points in the process where

the risk assessor must choose among “scientifically

plausible options. ” For example, one component

63-986 0 - 87 - 2
28

would be the number of animal studies needed

to be sure that the substance in question is truly

a carcinogen. Some people are willing to act based

on a single study in a single species, others want

confirmation in a second species.

An “inference guideline” consists of assumptions that must be made to estimate human risk.

The NAS Committee defined “risk assessment policy” as “the analytic choices that must be made

in the course of a risk assessment. Such choices

are based on both scientific and policy considerations” (137).

An agency might also adopt a risk management

policy for choosing among regulatory options. In

the committee’s view, risk management policies

should not be allowed to control risk assessment

policy. While risk assessment and risk management are commonly distinguished, both are based

on policy choices.

In addition to risk assessment guidelines and

risk management policies, agencies have developed guidelines for conducting and evaluating animal toxicity tests. To some extent, these testing

guidelines overlap with risk assessment guidelines.

For example, both might specify whether benign

tumors are to be considered with malignant

tumors when evaluating the results of animal tests.

Agency policies and guidelines have varied in

the degree of formality and in the basic approach

they take toward evaluating evidence for risk

assessments. Some policies, notably the cancer

policy issued by the Occupational Safety and

Health Administration (OSHA) and the sensitivity of method (SOM) guidelines proposed by the

Food and Drug Administration (FDA), are intended to be binding regulations and were subject to notice-and-comment rulemaking. Other

guidelines have been developed more informally

by agency staff, printed, and made available to

the public.

Rushefsky has classified agency carcinogen

policies into three types: presumption-rebuttal,

weight-of-the-evidence, and leave-it-to-the-scientists (180). The OSHA policy (276) represents the

presumption-rebuttal approach. This policy approach uses the regulatory process, establishes

“presumptions” and sets stringent conditions on

when and how these presumptions may be “rebutted. ” Other policies, particularly the latest policies of the White House Office of Science and

Technology Policy (OSTP) (351) and the carcinogen risk assessment guidelines of EPA (284) take

a weight-of-the-evidence approach, in which all

relevant data are used. A weight-of-the-evidence

approach is more flexible, and in implementation

by the agencies, is more open to considering negative, as well as positive, data on carcinogenicity. The OSHA policy, on the other hand, restricted the circumstances in which negative data

could be considered. In the third approach, leaveit-to-the-scientists, a separate body for conducting risk assessments is established. This represents

the clearest separation of risk assessment from risk

management. According to Rushefsky, only one

agency policy, a paper prepared by OSTP staff

in 1979 (23), adopts this approach, although other

proposals for creating centralized science panels

for developing or reviewing risk assessments are

of this type (for a discussion of these proposals

see ref. 217).

Interest groups have differed in their preferences

for the different approaches. Industry groups have

often supported various proposals to centralize

risk assessments, while labor, public interest, and

environmental organizations have opposed such

proposals. Industry groups have also strongly endorsed the weight-of-the-evidence approach. Because of the importance labor, public interest, and

environmental organizations place on the potential for harm to health, these groups want regulatory agencies to act on limited positive evidence

and often when industry thinks the weight of the

evidence does not support action.

Policies also vary in length, amount of detail,

and complexity. Some, like EPA’s “interim” guidelines of 1976 are only a few pages long, while,

for example, the explanation of OSHA’s policy

occupies nearly 300 pages in the Federal Register.

Utility of Policies

The NAS committee cited above recommended

that agencies adopt uniform risk assessment policies. Such guidelines have the advantages of

promoting quality control, consistency, predictability, public understanding, administrative efficiency, and improvements in risk assessment
29

methods. Potential disadvantages include oversimplification, inappropriate mixing of scientific

knowledge with risk assessment policy, misallocation of agency resources to guideline development, and the freezing of science (137). An important use of guidelines within the agencies is in

training junior staff in agency practices and procedures.

Some have hoped that risk assessment might

be conducted as a neutral, nonpartisan, scientific

enterprise. However, inference choices are necessary, and these, although often based on scientific understanding, are not empirically tested.

Some hypotheses are extremely difficult to test experimentally; for instance, determining the doses

that cause an increase in cancer risk of 1 percent

would demand the use of 1,600 laboratory animals. 2 Others raise ethical issues, for example,

evaluating the predictive value of animal test data

by exposing human subjects to suspect carcinogens to follow them prospectively. Political and

social values may also be reflected.

Policies may also reflect agency judgments on

the acceptability of errors. From a regulatory perspective, two risks must be balanced:

The first is the risk of taking precautionary action for a safe chemical (a regulatory false positive). The second is the risk of not controlling an

unsafe chemical . . . (a regulatory false negative)

(154).

The appropriate evaluation of an agency policy

would not then be seen in whether the agency correctly identified every carcinogen and every noncarcinogen and placed them into the correct categories. Evaluation should be based on the overall

success of the policy in improving public health.

An important part of this is considering the costs

of delaying public health protection (174). Some,

however, argue that agency efforts to adopt “conservative” assumptions for developing risk assess-

‘With a 95-percent confidence limit ranging from 0.5 percent to

1.5 percent (64).

HISTORY OF AGENCY POLICIES

The Food and Drug Administration

FDA was the first agency to set guidelines for

toxicity assessment. FDA has responsibility for

ments are misguided, leading to substantial overestimates of actual risks and distorting agency

priorities (149,178).

In addition, agency guidelines are not, by themselves, sufficient to surmount two regulatory hurdles: the different perspectives of various interested parties and the importance of case-by-case

interpretation.

In regulatory proceedings, the opinions of industry, labor, environmental groups, public interest organizations, and government are often

substantially different. These groups place different values on the harm caused by unnecessarily

regulating a chemical that later turns out to be

safe and the harm caused by not regulating a

chemical that turns out to be harmful. In a survey, Frances Lynn found evidence that there are

links between political values, place of employment, and scientific beliefs. For example, industry scientists in Lynn’s sample were less willing

to accept animal data on carcinogenicity and more

likely to believe in the existence of no-effects

thresholds for carcinogens (see the discussion below) than were government scientists (112). In

describing the history of Federal “cancer policies, ”

Rushefsky points to the importance of political

values in explaining some of the features of risk

assessment policies (179,180). Another source of

different perspectives is the various disciplines participants are trained in and the various scientific

paradigms they work under (86).

Even when the agencies have policies, there will

always be issues of interpretation in particular

cases, especially for “flexible” policies. For example, if a policy establishes five categories, questions will arise on which category applies to a particular chemical. Even accepting the value of

animal data in general, much regulatory debate

on carcinogens centers on whether a particular

animal study is reliable and on whether the data

apply in particular cases. Arguments on particular cases are not likely to disappear, especially for

commercially important chemicals.

regulating the safety of foods, drugs, cosmetics,

and medical devices. The 1958 Food Additives

Amendment to the Food, Drug, and Cosmetic Act

includes the Delaney clause, which proscribes the
30

intentional use of food and color additives determined to be carcinogenic in either humans or animals. This clause does not apply to all food ingredients because some were considered to be

“generally recognized as safe” or had been federally sanctioned prior to the 1958 amendment.

Nevertheless, the general FDA policy (until recently) has been to ban food and color additives

whenever they were determined to be carcinogenic. FDA has not explicitly specified any guidelines on interpreting carcinogenicity data.

FDA has specified the protocols for developing the animal data necessary to evaluate the

safety of food and color additives. FDA first published toxicity testing guidelines, consisting of a

series of papers by staff scientists, in a 1955 journal article (109). A revised version was published

as a book in 1959 (267).

In 1970, an FDA advisory committee on protocols for safety evaluation prepared a report on

designing experiments and on using animal data.

FDA also made recommendations, specifying the

use of at least two species, the maximum tolerated dose, and a two-generation bioassay design,

in which exposure begins prior to conception and

continues throughout the lifetime of the offspring.

Reflecting the state of the science then, the committee concluded that “at the present time there

is not enough information available to provide

a basis for recommending any rapid [i. e., shortterm] test for carcinogenicity” (247). In 1982, FDA

updated its guidelines on conducting animal toxicity tests (in the FDA “Red Book”) (248).

As described later in this chapter, in the 1970s

FDA began using quantitative risk assessments for

certain environmental contaminants found in

food. In the 1980s, FDA began applying these

techniques to food and color additives, both when

color additives are contaminated with small

amounts of carcinogenic impurities and when the

additive itself is determined to be carcinogenic.

(FDA procedures for using such risk assessments

are discussed in ch. 3.)

For animal drug residues in human food, the

“DES proviso, ” part of the drug amendments of

1962, prohibits carcinogenic drug residues that can

be detected by analytic methods approved by

FDA. For years FDA has been working on a regulatory definition of what these approved methods would entail. The general label for these regulatory requirements is “sensitivity of method”

or “SOM. ” SOM procedures were first proposed

in 1973, finalized in 1977, challenged in court,

withdrawn in 1978, and reproposed in 1979.

The 1973 proposal suggested use of a modified

Mantel-Bryan procedure for extrapolating from

effects at high doses to those at low doses (see the

discussion later in this chapter on extrapolation

models) and a risk cutoff of 1 in 100 million. This

number means that exposures at the permissible

limit would be associated with an upper bound

estimate of 1 in 100 million people exposed.3 In

1977, FDA issued a final rule keeping the MantelBryan procedure but changing the risk cutoff to

1 in 1 million. The reproposal in 1979, kept this

cutoff figure, but adopted linear extrapolation.

Subsequently, the responsibility for these regulations was transferred from FDA’s Center for

Food Safety to its Center for Veterinary Medicine.

The guidelines were then reproposed in October

1985 (246). An approved analytic technique is defined as one that could detect residue concentrations as low as the level associated with an upperbound human risk estimate of 1 cancer for every

1 million persons exposed. Of course, this technique requires a risk assessment to estimate what

residue levels correspond to this particular risk

level.

In 1968 and 1973, FDA published guidelines on

required toxicity information for investigating and

marketing new human drugs (67). These guidelines specified an 18-month rat study and a 12-

month study in dogs or monkeys, which was intended to cover both chronic toxicity and carcinogenicity. A 12-month rat study and a mouse

carcinogenicity study could be substituted for the

18-month rat study (67).

In the 1970s, FDA and the Pharmaceutical

Manufacturers’ Association (PMA) convened a

workshop to discuss toxicity testing for drugs, in3Agencies have not always distinguished clearly between risk estimates based on all cases of cancer and those based only on cancer

deaths. Depending on the tumor site, the two estimates can differ

(124). In this case, the FDA proposal referred only to “a minimal

probability of risk to an individual (e.g., 1/100,000,000) . . .“ (246).
31

eluding the length of carcinogenicity studies.

While the workshop had been convened with the

expectation that new guidelines would be issued,

FDA decided not to update its own guidelines at

that time. PMA, however, published guidelines

in 1977 that reflected the workshop’s consensus

in requiring longer duration studies in two species (67). For carcinogenicity study designs for human drugs, FDA staff also refer to the “Red Book”

guidelines for toxicity testing of food and color

additives, the documents published by OSTP, and

the report of the National Toxicology Program

(NTP) Ad Hoc Panel on study design (258). No

new formal guidelines for testing drugs have been

issued, although FDA staff state that they are being developed (249).4

Nevertheless, in reviewing new drug applications, there is general understanding between FDA

and industry about the evidence needed to obtain

approval. The kinds of tests needed depend on

the stage of clinical investigation and approval

process, and the expected duration of human use

of the drug (e. g., several days, up to 2 weeks, up

to 3 months, 6 months to unlimited use). (For a

summary, see ref. 218. )

For drugs expected to be continuously administered for 6 months or more, an application to

conduct a Phase I or Phase II clinical investigation must include the results of 3-month animal

toxicity studies conducted in two species. To initiate a Phase 111 trial, there must be information

from two species given the drug for 6 months or

more as part of ongoing studies of chronic toxicity and carcinogenicity. A New Drug Application

(for a drug intended for chronic or repeated use

in the general population) must now include the

results of 18- to 24-month chronic studies in two

rodent species (usually rats and mice) and a 12-

month chronic study in a rodent species and a

nonrodent species (e.g., dogs or monkeys).

FDA evaluates the evidence in the New Drug

Application for therapeutic efficacy and potential risks of the drug. If FDA judges that the risks

outweigh the benefits, the drug is not approved

for marketing. If the benefits are thought to out4

FDA has provided guidance for statistical analysis of data for

studies of human drugs, but this will not be discussed here.

weigh the risks, the drug is approved, but the

labeling for the drug will discuss potential hazards, including any animal evidence for carcinogenicity (66). For any particular drug, the final decision depends on how “persuasive” or “alarming”

the tumorigenic finding is, expected use of the

drug, and the nature of alternative therapies (69).

The Environmental Protection Agency

EPA began developing carcinogen assessment

guidelines during regulatory proceedings on the

suspension and cancellation of several pesticides.

In legal briefs written at the end of those proceedings, EPA attorneys summarized the expert testimony that the agency had received on evaluating

carcinogenicity. These summaries were referred

to as “cancer principles. ” (See box 2-A. )

Partly in response to criticism of these cancer

principles, EPA established a permanent organizational unit, the Carcinogen Assessment Group

(CAG), within EPA and developed a new set of

guidelines (9,122,137). In May 1976, EPA published “interim” guidelines for assessing the health

risks and economic impacts of suspected carcinogens (3,293). The text and explanation of these

guidelines occupied less than four pages in the Federal Register.

In November 1977, the Environmental Defense

Fund petitioned EPA to establish a policy on classifying and regulating carcinogenic air pollutants.

In October 1979, EPA published its proposed airborne carcinogen policy. This policy has never

been issued in final form, although agency staff

indicate that they follow the outlines of this policy (103).

EPA issued water quality criteria documents

under the Clean Water Act in response to a court

order to assess the hazards and risks posed by a

large group of substances. (See ch. 3 for details

on the development of this list. ) In March 1979,

EPA made available a methodology for assessing

human risk (methods for assessing other aspects

of water quality, e.g., the hazard to aquatic life

forms, had been prepared earlier). In November

1980, EPA announced the availability of the water

quality criteria documents and published sum-
32

Box 2-A.—Development of “Cancer Principles” at the Environmental Protection Agency

The substance of EPA “Cancer Principles” originated in the work of a group of scientists assembled

by National Cancer Institute (NCI) scientist Umberto Saffiotti. In 1970, the group prepared a report to

the Surgeon General, “Evaluation of Chemical Carcinogens.” This report responded to another report prepared by the Food Protection Committee of the National Research Council of the National Academy of

Sciences. This committee had suggested that regulators might allow potential carcinogens to be added to

foods at “toxicologically insignificant levels.” The committee also suggested that some substances might

be considered safe without undergoing testing, if they had “been in commerical production for a substantial period” and that a “no carcinogenesis level” might be shown for an animal species, although there were

no generally accepted ways of translating this threshold level to humans (122).

The 1970 report (250) by the Surgeon General’s ad hoc committee represents one of the first “guidelines” for evaluating potential carcinogens:

Any substance which is shown conclusively to cause tumors in animals should be considered carcinogenic and therefore a potential cancer hazard for man . . .

No level of exposure to a chemical carcinogen should be considered toxicologically insignificant for man.

For carcinogenic agents a “safe level for man” cannot be established by application of our present knowledge. The concept of “socially acceptable risk” represents a more realistic notion . . .

No chemical substance should be assumed safe for human consumption without proper negative lifetime biological assays of adequate size. The minimum requirements for carcinogenesis bioassays should provide for: adequate numbers of animals of at least two species and both sexes with adequate controls, subjected for their lifetimes to the administration of a suitable dose range, including the highest tolerated dose,

of the test materials by routes of administration that include those by which man is exposed . . .

Evidence of negative results, under the conditions of the test used, should be considered superseded by

positive findings in other tests . . .

The implication of potential carcinogenicity should be drawn from both tests resulting in the induction

of benign tumors and those resulting in tumors which are more obviously malignant. . . .

The principle of zero tolerance for carcinogenic exposures should be retained in all areas of legislation

presently covered by it and should be extended to cover other exposures as well. Only in the cases where

contamination of an environmental source by a carcinogen has been proven to be unavoidable should exception be made to the principle of zero tolerance. Exceptions should be made only after the most extraordinary

justification, including extensive documentation of chemical and biological analyses and a specific statement

of the estimated risk for man, are presented. All efforts should be made to reduce the level of contamination

to the minimum. Periodic review of the degree of contamination and the estimated risk should be made mandatory.

No substance developed primarily for uses involving exposure to man should be allowed for wide-spread

human intake without having been . . . tested for carcinogenicity and found negative. . . . Any substance

developed for use not primarily involving exposure in man but nevertheless resulting in such exposure, if

found to be carcinogenic, should be either prevented from entering the environment or, if it already exists

in the environment, progressively eliminated . . .

A unified approach to the assessment and prevention of carcinogenesis risks should be developed in

the federal legislation; it should deal with all sources of human exposure to carcinogenic hazards . . .

An ad hoc committee of experts should be charged with the task of recommending methods for extrapolating dose-response bioassay data to the low response region . . .

At the EPA hearings on canceling registration of DDT, Saffiotti included parts of the ad hoc committee report in his testimony. 1 In the brief, which summarized the evidence in the DDT cancellation decision

(315), EPA attorneys listed seven “general principles” for determining carcinogenic hazards that were drawn

from the ad hoc committee report:

1. Any substance shown conclusively to produce tumors in animals should be deemed potentially carcinogenic in man, except when the effect is caused by physical induction, or where the route of administration

is grossly inappropriate in terms of human exposure.

2. Carcinogenic data on man is acceptable only when it presents critically evaluated results of adequately

conducted epidemiological studies.

‘The NCI ad hoc committee report was also used by OSHA in justifying its “14-carcinogen standard. ”
33

3. No level of exposure to a chemical carcinogen should be considered toxicologically insignificant for man.

4. Carcinogenic bioassays should include two species of animals of both sexes, with adequate control animals, subject to lifetime administration of suitable doses, including highest tolerated doses, by routes of

administration including those by which man is exposed.

S. Negative results should be considered superseded by positive results, which should be deemed definitive,

unless new evidence conclusively proves that the positive results were not causally related to exposure.

6. An implication of potential carcinogenicity should be drawn both from tests which induce benign tumors

and those resulting in tumors more obviously malignant.

7. The principle of zero tolerance is valid and should be expanded.

In a subsequent proceeding concerning the pesticides aldrin and dieldrin, the EPA brief listed nine “cancer

principles”:

1.

2.

3.

4.

5.

6.

7.

8.

9.

A carcinogen is any agent which increases tumor induction in man or animals.

Well-established criteria exist for distinguishing between benign and malignant tumors; however, even the

induction of benign tumors is sufficient to characterize a chemical as a carcinogen.

The majority of human cancers are caused by avoidable exposure to carcinogens.

While chemicals can be carcinogenic agents, only a small percentage actually are.

Carcinogenesis is characterized by its irreversibility and long latency period following the initial exposure

to the carcinogenic agent.

There is great variation in individual susceptibility to carcinogens.

The concept of a “threshold” exposure level for a carcinogenic agent has no practical significance because

there is no valid method for establishing such a level.

A carcinogenic agent may be identified through analysis of tumor induction results with laboratory animals exposed to the agent, or on a post hoc basis by properly conducted epidemiological studies.

Any substance which produces tumors in animals must be considered a carcinogenic hazard to man if the

results were achieved according to the established parameters of a valid carcinogenesis test (quoted in 122).

In its notice proposing to suspend registration of the insecticides chlordane and heptachlor, EPA set forth

principles very similar to these nine statements. Organizations, particularly from industry, and individuals

outside EPA expressed concern about the principles’ substantive content, and EPA staff scientists became

concerned that these scientific principles had been formulated by EPA attorneys.

Later, Saffiotti prepared a draft summarizing 17 principles of carcinogenesis that had been used in

previous proceedings. EPA attorneys attempted to have these principles included as “officially noticed facts”

in the proceedings concerning the pesticide Mirex, Apparently a storm of protest followed, after which

the 17 principles were reduced to “three basic facts”:

1. There is presently no scientific basis concluding that there is a “no effect” level for chemical carcinogens.

2. Experimental data derived from mouse and rat studies can be used to evaluate whether there is a cancer

risk to man.

3. All tumorigens must be regarded as potential carcinogens. For purposes of evaluating carcinogenicity hazard, no distinction should be made between the induction of tumors diagnosed as benign and the induction

of tumors diagnosed as malignant (quoted in 122).

In April 1976, the Administrator of EPA decided that, while these proposed “facts” represented the

best available evidence and were valid for supporting regulatory action, he wasn’t prepared to designate

them as “officially noticed facts” (122).

In 1975, while the effort to transform the principles into “officially noticed facts” was pending, an

EPA scientist asked NCI to review EPA’s cancer principles. This question was referred to a Subcommittee

on Environmental Carcinogenesis of the National Cancer Advisory Board, which was asked in September

1975 “to develop general criteria for use in the assessment of whether specific environmental agents constitute a carcinogenic hazard in humans. ” EPA later withdrew its request for this effort, but the subcommittee, chaired by Phillipe Shubik, met in November 1975. The subcommittee finished a document in June

1976 that covered issues related to the identification of carcinogens (348). The report cautions that evidence of hazards must be evaluated case by case and that “criteria appropriate for one agency may not

necessarily apply to another. ” In other respects, the conclusions of this report were similar to those in the

other lists of “principles. ”
34

maries of the documents in the Federal Register.

The policy described later in this chapter is found

in an appendix to that announcement. The major change from the 1979 methodology to that described in 1980 was EPA’s adoption of the linearized multistage model for extrapolating from high

to low doses. The appendix describing carcinogen risk assessment was prepared by the staff of

CAG. This publication was the most extensive explanation of their procedures available at that

time.

In 1984, EPA published a proposed revision of

its carcinogen assessment guidelines (309). EPA’s

purpose was “to promote quality and consistency

of carcinogen risk assessments within the EPA and

to inform those outside the EPA about its approach to carcinogen risk assessment.” The guidelines were to “provide general directions for

analyzing and organizing available data” and were

not intended to alter risk management policies established under the various statutes administered

by EPA. Also in November 1984, EPA published

proposed guidelines for exposure assessment (310)

and for mutagenicity and developmental toxicants

risk assessments (311,313). Shortly thereafter, it

published proposed guidelines for risk assessments

of chemical mixtures (312). After making revisions

and waiting for the Office of Management and

Budget (OMB) to complete its review, EPA published the final version of these guidelines in September 1986 (284,285,286,287).

These last guidelines on carcinogen risk assessment consist of 10 pages in the Federal Register,

describing the “general framework” to be used in

assessing carcinogenic risk and “some salient principles to be used in evaluating the quality of data

and in formulating judgments concerning the nature and magnitude of the cancer hazard from suspect carcinogens” (284). This policy outlines the

various steps of risk assessment: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Finally, the policy

presents a “weight-of-the-evidence” classification

system, with five basic categories. A chemical will

be classified based on the nature (sufficient, limited, inadequate, etc. ) of the evidence from human

and animal studies. This classification has acquired important regulatory implications because

EPA’s Office of Drinking Water uses it to set recommended limits in drinking water and EPA’s Office of Emergency Response uses it as part of a

ranking system for adjusting reportable quantities of hazardous substances covered by the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, commonly

known as Superfund).

The Consumer Product Safety

Commission

The Consumer Product Safety Commission

(CPSC) published carcinogen assessment guidelines in 1978 and made them effective immediately

(229). At the same time, CPSC provisionally classified perchloroethylene as a suspect carcinogen

using the policy. Dow Chemical Company sued,

claiming that even such a provisional classification harmed Dow. The court held that CPSC

could not use the cancer policy in this manner until it was adopted in rulemaking procedures (45).

Subsequently, CPSC formally withdrew its cancer policy from the rulemaking process and

decided to use the guidelines adopted by the Interagency Regulatory Liaison Group (IRLG), and

more recently the guidelines issued by OSTP.

(Even though CPSC’s policy was withdrawn, its

contents are still interesting in light of other Federal agency policies, and for this reason, the policy is discussed further below. )

The Occupational Safety and

Health Administration

OSHA published a proposed regulation governing identification and regulation of carcinogens

on January 20, 1977. OSHA held hearings, accumulated an extensive record, and published a final regulation in 1980. One important purpose of

the policy was to improve the efficiency of the

standards-setting process. OSHA officials argued

that the slowness in setting standards was partly

related to the many discussions, arguments, and

lawsuits involved in every regulatory proceeding

on carcinogens (365). The proposed policy generated considerable controversy about OSHA’s

identification and regulation of carcinogens, and

dispute about the fraction of cancer incidence in

the United States that can be attributed to occupa-
35

tional exposures. (See refs. 217 and 159 for discussions of this second issue. )

OSHA published its carcinogen policy as a

binding regulation. Its intent was to collect evidence and testimony on “generic” issues in carcinogen identification and regulation, make decisions on these issues, and then rely on these

decisions in future proceedings. (The policy uses

a “presumption-rebuttal” approach (180). ) The

framers of this policy hoped that its use would

speed the regulation of carcinogens by limiting debate about generic issues in the regulatory proceedings on individual carcinogens.

In contrast to other agencies’ adoption of quantitative risk assessments for setting standards, the

OSHA cancer policy stated that quantitative risk

assessments would be used only to set priorities.

Originally, some of the provisions of OSHA’s carcinogen policy concerning risk management stated

that once OSHA determined a substance to be a

carcinogen, it would then set an exposure standard based only on feasibility. In 1981, OSHA

amended its carcinogen policy to conform to the

Supreme Court decision on OSHA’s benzene

standard, which provided that OSHA could only

regulate exposures posing a “significant risk” to

the health of workers and only if the regulation

would significantly reduce the risk. The amendment allowed OSHA to consider the significance

of estimated risk and feasibility in setting health

standards for carcinogens. Regarding the specifics

of risk assessment, OSHA did not change its judgments on the science of identifying carcinogens,

although it did indicate that certain types of evidence and arguments that it had originally hoped

to exclude from specific proceedings might be relevant to determining whether there was a significant risk. OSHA policy was also amended to

reflect this conclusion (274). In 1982, OSHA suspended parts of the policy that required publication of lists of candidate carcinogens (after one

list had been published in 1980) and requested

public comment on more general issues concerning the substance of its policy (275). As yet, no

changes have been made in the policy based on

those comments. The policy was legally challenged by industry groups shortly after it was published in 1980, although the case was never argued and the suits have been dismissed.

Other Agencies and

Interagency Efforts

OSTP and several interagency committees have

worked on carcinogen assessment guidelines and

regulatory policies. The Carter Administration

established the IRLG, which initially had representatives from EPA, CPSC, OSHA, and FDA.

Later, the Food Safety and Quality Service of the

Department of Agriculture (USDA) joined. An

IRLG working group, consisting of scientists from

the IRLG agencies, the National Cancer Institute

(NCI), and the National Institute of Environmental Health Sciences (NIEHS), published “Scientific Bases for Identification of Potential Carcinogens and Estimation of Risks” in July 1979.

The report is noteworthy because it represents the

first joint attempt of regulatory agencies to develop a consistent approach to identify carcinogens. However, some differences of opinion remained, especially concerning the desirability of

quantitative risk assessment (137).

Another interagency group in the Carter

Administration, the Regulatory Council, also prepared a document on carcinogen regulation. The

Regulatory Council’s conclusions on the science

of identifying carcinogens relied heavily on the

IRLG document, which was published as an appendix to the Council’s document (354).

In 1979, several staff members of OSTP prepared a document to “stimulate development of

a uniform decision-making framework to assure

consistent Federal action regarding the identification, characterization, and control of potential

human carcinogens.” Making a distinction between “scientific data collection and analysis” and

“regulatory decision-making, ” it examined only

the former. This document was relatively short,

consisting of short discussions of particular areas

and giving the authors’ recommendations for improvements in Federal decisionmaking. In particular, they suggested the coordination of Federal risk

assessment activities under the aegis of NTP (23).

In 1981, the new Reagan Administration articulated a strong opposition to most government

regulation. Even before the inauguration, David

Stockman, the first Director of OMB under the

Reagan Administration, had published a list of
36

regulations he thought were undesirable. Within

2 months of taking office, Reagan created a task

force on regulatory relief, chaired by the Vice

President, and issued an Executive order providing for OMB review of agency regulatory proposals and final rules. The order stated that agencies could regulate only when the benefits of

regulation exceeded its cost, except when this was

prohibited by law. Administration officials asked

affected businesses to inform them about regulations the businesses wanted changed. In 1981 the

Reagan Administration also dissolved IRLG and

the Regulatory Council.

In 1982, several events suggested the beginnings

of a decidedly different approach to assessing carcinogenicity. In that year, EPA decided not to designate formaldehyde for priority review under the

Toxic Substances Control Act (TSCA). In a memo

to EPA Administrator Anne Burford, John Todhunter, EPA’s Assistant Administrator for Pesticides and Toxic Substances, concluded that while

formaldehyde appeared to be carcinogenic in rats,

the carcinogenic potential of formaldehyde also

seemed to “vary significantly with species and

route.” Moreover, although in certain exposure

situations, formaldehyde could pose a human

risk, the available epidemiologic information

“supports the notion that any human problems

may be of low incidence or undetectable. ”

Quantitative risk estimates fell into a range that

Todhunter considered low. For these reasons, he

did not think formaldehyde should be subject to

an accelerated review under TSCA (155,196).

A second EPA document appearing in 1982 was

a draft of guidelines for assessing carcinogenicity, specifically for developing water quality criteria. The draft described a weight-of-the-evidence

stratification scheme, modeled after the scheme

of the International Agency for Research on Cancer (IARC),5 and suggested that regulatory distinctions be made between carcinogens that act

by causing gene mutations and those that act by

different mechanisms. For the latter, the draft suggested development of water quality standards

using the “no observable effect level” (NOEL)

(180,279). In 1983 it was also revealed that Rita

5EPA later adopted such a scheme in its 1986 policy, as discussed

below.

Lavelle had written a memo urging that trichloroethylene (TCE) be reevaluated and that EPA develop a “threshold model risk assessment for nongenotoxic chemicals such as TCE” (117).

A third draft document represented an administrationwide effort to revise agency practices on

carcinogenicity risk assessment. In 1982, as part

of the Reagan Administration’s efforts to reduce

the burden of government regulations and to develop a “scientifically sound basis for identifying

and characterizing potential human carcinogens, ”

OSTP convened an interagency committee to update the information contained in the 1979 IRLG

document. The committee developed a “rough

first draft” statement on “the current state of the

science” (105).

The draft, which criticized many of the existing procedures used by regulatory agencies including the use of high-dose testing in animals and linear non-threshold extrapolation models, suggested

distinctions based on mechanisms of action (e.g.,

between epigenetic and genotoxic agents) and the

greater use of pharmacokinetic information in risk

assessments (180).

The draft was circulated among a number of

scientists and generated considerable controversy.

Criticism especially focused on a chapter by John

Todhunter, which suggested distinctions based on

mechanisms. Congressional committees held hearings on this and other aspects of the Administration’s regulatory policies in 1982 and 1983. In the

wake of several revelations not directly related

to the ongoing effort to develop “science principles” for carcinogenesis, most of the top EPA officials left office (362).

Review of the scientific basis for carcinogen risk

assessment continued under Ronald Hart, the Director of FDA’s National Center for Toxicological Research (NCTR). Drawing on scientists from

NIEHS, NCI, NCTR, OSHA, CPSC, FDA, EPA,

USDA, and OSTP, another draft was prepared

and published for public comment and was generally received favorably (116).

A final version, “Chemical Carcinogens: A Review of the Science and Its Associated Principles,

February 1985,” was published by OSTP in March

1985 (351). It was republished in the journal Envi-
37

romnental Health Perspectives in 1986 under the

authorship of the U.S. Interagency Staff Group

on Carcinogens, reflecting the contributions of

staff from all the agencies involved. This document is an extensive summary of the state of various scientific fields underlying risk assessment:

mechanisms of carcinogenesis, short-term tests,

long-term bioassays, epidemiology, and exposure

assessment. The document concluded with a discussion of the assumptions used in the process of

risk assessment and included a series of summary

principles.

GUIDELINES FOR CONDUCTING CARCINOGENICITY TESTING

Toxicity testing and interpreting test results are

important features of several Federal regulatory

and research efforts aimed at preventing exposures

to carcinogens. In some circumstances, toxicity

testing may include long-term bioassays to determine directly whether substances cause cancer in

animals. Several laws that provide for carcinogen regulation allow Federal agencies to order regulated industries to conduct toxicity tests. The

Federal Government’s own carcinogenicity bioassay program was once housed at NCI, but is now

coordinated by NTP. (See ch. 4.)

Required Carcinogenicity Testing

FDA requires carcinogenicity testing for some

substances that are proposed as new, direct food

or color additives. Decisions on whether a substance must be tested are made using a complex

scheme based on the chemical structure of the substance (e. g., its chemical relation to known carcinogens) and the expected concentration of the

substance in food. These two factors are used to

classify the substance into one of three “concern

levels.” Only for the highest level are lifetime carcinogenicity bioassays required. For the other two

levels, FDA requires that the substance be tested

in a battery of short-term tests. The results of the

short-term tests may alter the concern level of the

substance and thus lead FDA to require a longterm bioassay.

For animal drugs that may leave potentially

harmful residues in food, FDA uses three kinds

of information to decide whether to require carcinogenicity testing:

● the potential toxicity of the drug, which is

evaluated based on chemical structure and

short-term and subchronic tests;

● the estimated level of use in food-producing

animals; and

Ž the amount of drug residue expected to be

consumed by a person during a single exposure.

For human drugs, FDA requires carcinogenicity testing for any new drugs expected to be used

for chronic or repeated use, although these requirements are not found in any written guidelines or regulations. These requirements apply to

new drugs and not to drugs that were approved

prior to 1968 when FDA began to require chronic

tests.

Under the Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA), EPA may require animal carcinogenicity studies for registering new

pesticides and reregistering existing pesticides. A

carcinogenicity bioassay is required for these substances in three specific circumstances:

1.

2.

3.

when the active ingredients, metabolizes,

degradation products or impurities are structurally related to recognized carcinogens,

cause mutations in short-term tests, or produce a worrisome effect in subchronic

studies;

when use of the pesticide will require that

EPA or FDA issue a food tolerance limit or

food additive regulation; and

when use of the pesticide will result in significant human ‘exposure (e.g., in fabric

treatments, insect repellents, and indoor pesticides).

Under TSCA, EPA may require testing either

for new chemicals entering the market or for existing chemicals. In the latter case, EPA must conclude, first, that the chemical may present an unreasonable risk to health or the environment or

that it may or will enter the environment in large

quantities or present significant or substantial hu-
38

man exposures; and, second, that testing is necessary to provide more information about the

chemical.

Analysis of Test Designs

In this section, OTA compares the carcinogenicity bioassay study designs required for food

and color additives (245), for chronically used human drugs (161), for pesticides (332), and for tests

ordered under TSCA (318). For animal drug carcinogenicity studies, FDA has not adopted separate guidelines but instead refers drug sponsors

to the NCI test guidelines (251) and to the 1971

and 1982 versions of the guidelines for food additive testing (245,247). NCI developed a standard design for federally funded tests and published

it in 1976 (251). NTP conducts most of its tests

through the use of contract laboratories and,

through its contractual “statement of work, ” sets

the design of these studies (256). In addition to

study designs used by NCI and NTP, the comparison covers the recommendations of a group

of scientists whose findings were published by

IARC (59) and of a panel of outside scientists convened by NTP (258). This comparison covers only

written requirements and suggestions. OTA has

not attempted to determine how well the conducted bioassays comply with these guidelines.

Not all regulatory agencies have specified guidelines for test design. OSHA, for example, rejected

the specification of test protocols and data analysis in favor of reliance on informed scientific

judgment. In part, as OSHA pointed out, this reflects its own regulatory purposes-OSHA uses

whatever test data are available and does not require toxicity testing. FDA and EPA, on the other

hand, can require industry to test.

General Provisions for Test Designs

Today there is relatively little controversy

about the general design of carcinogenicity

studies, and guidelines are relatively consistent in

their requirements for study design. The basic

study design uses two different animal species. Because of the relatively low cost and long experience using rats and mice, these two species are

usually used. The animals must be free of disease

and quarantined, then they are randomly assigned

to different groups.

Exposure routinely begins by the time the animals are 6 weeks old and the study ends usually

after 2 years of exposure. Exposure is preferably

through the route that most closely imitates human exposure. For example, food additives should

be tested by adding the suspect additive to the animals’ feed, while airborne toxic substances should

be tested by mixing the substance into the air the

animals breathe.

Animals are randomly assigned to two or three

treatment or exposure groups and a control group,

which is not exposed at all. Care must be taken

to ensure that the exposed animals and the control animals live under the same conditions, except for the exposure to the suspect substance.

Animals that die during the study are examined

for signs of toxicity and for tumors. At the end

of the study, all the surviving animals are killed

and necropsy is performed. The various guidelines specify a complete examination for visible

lesions and tumors, and list the organs that are

to be prepared for microscopic examination, although they differ on the extent of microscopic

examination required. After tumors have been diagnosed, statistical analyses are used to determine

whether the exposed groups had a higher incidence of tumors than the control group.

Issues in Test Design

Table 2-1 presents several main issues in the design of carcinogenicity bioassays and the way they

are handled by the various guidelines. As outlined

in OTA’s 1981 report, Tehnologies for Determining Cancer Risks From the Environment, the principal issues in study design are the following:

●

●

●

●

study plan, including the selection of animal

species, the number of animals for each dose

level, and the dose levels themselves;

dosing regimen, including the age at which

to begin exposure, when to terminate exposure, and whether there should bean observation period between the end of exposure

and the sacrifice of the animals;

pathology, including the nature of the autopsy examination of the animals and the extent of microscopic examination; and

personnel qualifications.
39

In addition, some of the guidelines discuss survival criteria, such as the number of animals that

must survive to have a valid positive or negative

study.

Some differences in terminology exist, but the

guidelines are generally consistent about the important issues in study design. All the guidelines

require that two different species be tested. NCI

and NTP guidelines specify the strains of rats and

mice to be used by testing programs. EPA’s guidelines and PMA’s drug testing guidelines specify

the rat and the mouse as test animals, while the

FDA “Red Book, ” IARC scientists, and the NTP

Ad Hoc Panel suggest considering hamsters. The

Ad Hoc Panel further encourages the search for

other species for carcinogenicity testing.

All the guidelines specify that testing shall be

done in both males and females, and all but 1 set

of guidelines specify the size of each test group

as 50 animals per dose. The NTP Statement of

Work specifies 60 animals per dose, including 10

animals scheduled for interim sacrifice between

the 12th and 18th month of the study. Several

other guidelines mention that the number of animals should be increased if the researchers want

to conduct an interim sacrifice, although no other

guidelines require interim sacrifice. The number

of animals needed for the chronic phase of testing depends on the number of doses.

NCI and PMA guidelines require at least two

dose groups in addition to the control group.’ All

the other guidelines suggest the use of three dose

groups and the unexposed control group. With

50 male rats, 50 female rats, 50 male mice and

50 female mice for each exposure level, a study

using 2 exposure levels and controls uses 600 animals, a study with 3 exposure levels and controls

requires 800.

All the guidelines provide that the highest dose

level should be based on information gathered in

a subchronic toxicity study (usually lasting about

90 days). However, slightly different terminology

is used to refer to this dose level. The most common term in the toxicologic literature is “maximum tolerated dose” or MTD. Most of the guide-

“Today, however, virtually all drug carcinogenicity studies are

conducted with three dose groups (249).

lines refer instead to the “high dose level” or “high

dose, ” perhaps to avoid the controversy that

“maximum tolerated dose” has engendered. (As

discussed below in the section on agency risk

assessment policies, the reason for high-dose testing is to enable a study to best detect a carcinogenic response. )

In general terms, the high dose should be as

high as possible without shortening the animals’

lives from noncarcinogenic toxic effects. FIFRA,

TSCA, and “Red Book” guidelines specify that the

dose should be minimally toxic without substantially altering the normal lifespan of the animal.

The NTP Statement of Work and NTP Ad Hoc

Panel documents also state that the high dose

should not affect the animals normal lifespan from

effects other than carcinogenicity. NCI guidelines

give more detail: the MTD should neither alter

the lifespan (other than from carcinogenicity),

clinical signs of toxicity, or pathological lesions

(other than neoplasms) that shorten the animals’

lives nor should it lead to more than a 10-percent

decrement in weight gain in experimental animals

relative to controls. PMA guidelines specify that

the highest dose should be “slightly below toxic

dose,” without providing any further guidance.

Important to the success of a bioassay is the

professional judgment of the researchers conducting the study and analyzing the data from prechronic studies. To some extent, setting the highest dose requires an educated guess.

The low doses are often defined as fractions of

the highest dose. For example, NCI guidelines set

the second dose as one-half or one-fourth of the

MTD. (This formula is also given by IARC scientists for studies aimed at only a qualitative determination of a substance’s carcinogenicity. )

PMA guidelines specify that the second dose

should be greater than or equal to the expected

equivalent human dose, but less than or equal to

half the high dose. The FDA “Red Book” and

TSCA guidelines specify the lowest of three doses

to have “no indication of toxicity” and, generally,

to be 10 percent of highest dose (FDA) or not less

than 10 percent of the highest dose (TSCA). IARC

scientists suggest, for studies gathering quantitative information, that the doses be scaled by factors of 3, 5, or 10, The NTP Ad Hoc Panel and

TSCA guidelines mention that researchers should
Table 2.1 .—Test Design Issues

NTP-statement of NTP Ad Hoc Comm. FDA-food & color FDA/PMA-drugs

NCI (251) work (256) (258) IARC (59) additives (248) (161) TSCA (318) FIFRA (332)

2; choose among

rats. mice, hamsters

2, rodents: rats

mice, hamsters

2, rats & mice (pick

strains w/low background incidence)

2. rats & mice 2, rats & mice preferred

Animal species ‘2, NCl used primarily

B6C3F1 mice &

Fischer 344 or

Osborne-Mendel rats

2, B6C3Fl mice &

Fischer 344 rats (unless NTP specifies

otherwise)

Recognizes rats,

mice, hamsters as

most popular, encourages search for

other species

60 male, 60 female

(allows for interim

sacrifice of 10

animals)

50 male, 50 female;

for special studies,

number of groups &

distribution may be

altered

3 plus control. MTD

identified in

prechronic studies as

dose which will not

Impair normal longevity from effects

other than induction

of tumors; use metabolic/pharmacokinetic studies to select lower doses;

route should be same

as human exposures,

if using gavage, conduct pharmacokmetlc

studies to back up,

explore alternates

to vegetable oil

gavage

50 male, 50 female 50 male, 50 female

(increase for interim

sacrifice)

50 male, 50 female 50 male, 50 female

(increase to allow for

interim sacrifice)

50 male, 50 female

(Increase to allow for

interim sacrifice)

Number at each 50 male, 50 female

dosage

Dosages At least 2 PIUS control, MTD & MTD/2

or MTD/4, MTD defined as ‘‘highest

dose that can

be predicted not to

alter the animal

Iongevity from affects

other than carcinogenicity’ i. e , no more

than 10% weight

loss, no mortality or

clinical signs of toxicity that shorten animal’s Iife, desirable

to have positive control group

3 plus control, high

dose iS “predicted

not to alter normal

Iongevity of the animals from effects

other than carcinogenicity’

2 plus control for

qualitative studies, 3

or more for studies

to be used for quantitative assessment,

select high dose “as

one that produces

some toxicity but not

appreciable cell

death or organ dysfunction, toxicity that

impairs Iifespan

(other than tumors)

or more than 10%

decrement in weight

gain compared to

controls; lower

doses. qualitative

MTD/2 to MTD/4,

quantitative: scale by

factors of 3,5,10

3 plus control, high

dose should elicit

minimal toxicity w/o

substantially altering

lifespan (other than

effects related to

tumors); lowest dose

should induce no

signs of toxicity

(generally 10% of

high dose); intermediate dose should

be approx midway,

depending on pharmacokinetics

2 or more plus control, high dose–

slightly below toxic

dose, low dose–

greater than or equal

to human dose level

& less than or equal

to one-half of high

dose

3 plus control, highdose Ievel–minimally

toxic w/o substantially altering normal

lifespan, lowest

dose–should not ininterfere w/normal

growth or show any

other signs of toxicity, should not be

less than 10% of

high dose, intermediate—m between, depending on toxicokinetic properties, if

known

3 plus control, highest dose level should

be sufficiently high

to elicit signs of minimal toxicity w/o

substantially altering

the normal lifespan

Required number Terminate when sursurviving/Termmatlon vival reaches 10%

criteria within group

May terminate when

cumulative mortality

jeopardizes ability to

draw conclusions on

carcinogenicity: contractor must consult

with NTP

Not satisfactory if

mortality exceeds

50% before week

104 for rats, week

96 for mice; end

study when mortality

in control or lowdose groups equals

75%

Survival must be at

least 50% at 24

months (rats) & 18

months (mice), no

more than 10% lost

due to autolysis,

cannibalism, or management problems,

may terminate ‘under special circumstances’ if there are

only 10 survivors m

any group after 24

months (rats) or 18

months (mice), but

minimum survival

criteria must be met

Terminate if mortality

reduces control

group to less than

40% of original number of animals per

sex

For valid negative

study, survival must

be greater than 50%

in all dose groups at

24 months (rats) or

18 months (mice) &

less than 10% loss

due to autolysis,

cannibalism, or management problems

Survival must be at

least 50% at 18

months (rats) or 15

months (mice) & at

least 25% at 24

months (rats) or 18

months (mice)

continued on next page
As soon as possible

after weaning, Ideally

before 6 weeks not

later than 8 weeks

As soon as possible

after weaning, Ideally

before 6 weeks, not

after 8 weeks

Begin exposure to

parents prior to mating, exposure m

utero & for life of

offspring for nonnutritive additives &

certain other substances

At least 104 weeks,

up to 130 weeks

“Weaning animals

have often been

used, but suggests

prenatal design may

be more sensitve,

recommends data de

velopment on this

Start of dosing Weanings if possI- 6-7 weeks old

ble, no older than 6

weeks

Consider starting ex- –

posure in utero m

certain cicumstances

Duration of dosing

Observation period

‘‘Greater part” of

the animals’

lifespan–24 months

103 weeks (plus up

to 2 more weeks to

schedule necropsles)

NTP should do

studies to determine

optimal endpoint

24 months for rats,

18 months for mice

24-30 months for

rats, 8-24 months for

mice

At least 24 months

for rats, at least 18

months for mice

See termination criteria above, in any

case, no longer than

130 weeks for rats,

120 weeks for mice

Prefers no observation period, if

desired, treat to 104

weeks for rats 96

weeks, for mice

24-30 months for

rats, 18-24 months

for mice

May be desirable to

hold animals for additional 3-6 months

1 week Recommends against

ending exposure

prior to sacrifice unless there IS concern

about exposure to

technicians

— —

Continuous, 7 days

per week IS preferable; 5 days per

week IS acceptable

Dosing frequency 7 days/week for

food/water exDosure,

7 days per week,

use oral exposure

route

Ideally 7 days per

week; 5 days per

week acceptable,

oral route preferred

provided substance

iS absorbed m GI

tract

Full histopathology

on: 1) all animals m

control & high dose

groups & all that

died during study, 2)

all gross lesions, 3)

target organs, 4)

lungs, liver & kidneys m all animals,

if there were problems with high dose

group, use next

lower group for full

histopathology

— — — —

otherwise based on

human exposures

Gross exam of all;

detailed histopathology on high dose &

control groups; if no

difference is found,

then histology can be

restricted to examining gross lesions &

sites where significant lesions are observed in high dose

group; suggests distinguishing between

fatal & incidental

tumors, especially for

statistical analysis

Gross exam for all

animals, microscopic

exam for: 1) all visible tumors, 2) all

animals that died

during study, 3) high

dose group & controls. If significant

difference is seen,

then examine the

particular organs/tissues in all

animals

Microscopic exam of

1 ) all gross lesions,

2) complete set of

tissues of all high

dose survivors &

controls; if questionable, then examine other exposure

groups

Full histopathology

on: 1) all animals in

control & high dose

groups & all that

died during study, 2)

all gross lesions, 3)

target organs in all

animals; if there

were excessive early

deaths or problems

with high dose

group, use next

lower dose group for

full histopathology

Organs & tissues

examined

All animals gwen

gross exam;

histopathology for: 1

gross lesions/suspect tumors, 2) list

of organs for all

treated & control

animals

All animals given

gross exam; full

histopathoiogy for all

treated & control

animals

All animals gwen

thorough examination; consider alternatives to reduce

burden of histopathology, such as

inverse pyramid &

selected inverse

pyramid

Study director – Doctorate m toxicology, pathology, veterinary medicine,

biochemitry, or

chemistry

— Appropriately educated, trained, & experienced toxicologist— — —

Pathologist

Histology technicians

Board-certified w/ex- Formal training & experience required,

board cerification

desirable

4 ‘Individual possessing expertise m laboratory animal

pathology’

Board-certified or

board-eligible or person w/equivalent

training w/expertise

Certified by

HT/ASCP or having

equivalent traimng &

capability

— —

perience in laboratory

animal pathology

Supervised by ASCP-registered

technicians

— — —

HT/ASCP technician

SOURCE office Of Technology Assessment based on recorded documents

—

.,
42

use information on metabolism and pharmacokinetic studies, if available, to help set dose levels.

The control group should be completely untreated or sham treated, and should otherwise be

handled by the lab workers in the same way as

the treated animals. Sometimes control animals

are treated with the “vehicle” used to administer

the test compound, such as the corn oil used in

gavage studies (vehicle controls). Sometimes, researchers will also include a group of animals to

be exposed to a known animal carcinogen (positive control), to be sure that the animals being

used are in fact sensitive to a known carcinogen.

Except for the NCI guidelines, the guidelines that

mention this possibility generally include it for

routine studies. IARC scientists state information

should be collected on control animals to evaluate any changes over time.

The basic laboratory alternatives for dosing the

animals include adding the substance to the animals’ food or water, exposing the animals by contaminating their air in special inhalation chambers, painting the substance onto the animals’

skin, or delivering the substance, usually dissolved

in corn oil, directly into the animals’ stomachs

using a special tube (gavage studies). With regard

to the dosing regimen, the guidelines provide that

the route of administration be as close as possible to the human exposure route, recognizing that

sometimes this is not possible, for example, when

the suspect compound is so unpalatable that animals will not eat the treated feed. For dosing in

food or water, exposure is generally 7 days per

week. For inhalation or gavage studies, laboratories generally expose the animals five times per

week to match the schedules of laboratory personnel.

The guidelines also specify the age of the animals at the start of the study. The NCI, NTP

Statement of Work, FDA “Red Book,” TSCA, and

FIFRA guidelines all require dosing to begin

shortly after the animals have been weaned and

before the animals reach 6 to 8 weeks. For food

and color additives, FDA often requires the manufacturer to conduct the carcinogenicity study in

at least one rodent species with in utero exposures.

Parents are exposed to the test compound prior

to mating, and exposure continues through pregnancy and throughout the lives of the animals.

It is argued that this design is particularly sensitive

in detecting carcinogenic effects and is especially

appropriate for substances in the food supply because exposures may be continuous for parents

and children. PMA guidelines also mention the

in utero design as a possibility, although data on

this design are lacking. The guidelines suggest use

of the design to develop data, especially for drugs

that may be used in childbearing women. The

NTP Ad Hoc Panel also suggests that the in utero

design be considered under certain circumstances.

The guidelines differ concerning when a study

should end. The basic principle is that carcinogenicity studies should expose the animals for the

“greater part of the animals’ lifespans” (251). For

rodents, this is generally considered to be 2 years.

Thus, the NCI guidelines provide for exposures

of 24 months, the NTP Statement of Work provides for 103 weeks (plus up to 2 more weeks to

schedule autopsies), and the FDA “Red Book” requires at least 104 weeks (24 months), though such

a study may last up to 130 weeks (30 months).

PMA, TSCA, and FIFRA guidelines provide for

a shorter exposure for mice: 18 months for PMA,

at least 18 months for FIFRA, and 18 to 24 months

for TSCA. For rats, these guidelines provide for

studies of at least 24 months.

NCI guidelines suggest it “maybe desirable to

hold animals for an additional period of 3-6

months” after exposure has stopped. This time

was termed an “observation period. ” More recently, however, the NTP Ad Hoc Panel concluded that, except when there is concern about

exposure to lab personnel, “it does not seem wise

to terminate exposure prior to sacrifice.” The NTP

Statement of Work sets a l-week period for observation. FIFRA guidelines say that rat studies

may be 24 to 30 months long and mouse studies

18 to 24 months long.

IARC scientists define the length of a study in

terms of the animals’ survival. According to them,

a study should be terminated when 75 percent of

either the control or low-dose group have died.

But in no case should the study extend beyond

130 weeks (30 months) for rats or 120 weeks (28

months) for mice. IARC prefers no observation

period, but suggests that if one is desired, treat-
43

ment can continue 104 weeks for rats and 96

weeks for mice.

NCI guidelines provide for the termination of

a study when survival drops to 10 percent in any

group. The NTP Statement of Work allows for

termination when “cumulative mortality jeopardizes ability to draw appropriate conclusions on

carcinogenicity,” but requires consultation with

NTP before a contractor can sacrifice the animals.

The FDA “Red Book” provides that a study may

be terminated “under special circumstances” if

there are only 10 surviving animals in any group

(because these groups contain 50 animals, this is

a survival rate of 20 percent) after 24 months in

rats and 18 months in mice.

The FDA “Red Book,” TSCA guidelines, FIFRA

guidelines, and IARC scientists specify the minimum survival necessary for a valid negative

study. The FDA “Red Book” requires at least 25

animals per sex at 24 months for rats and at 18

months for mice. In addition, no more than 10

percent of the animals should have been lost due

to autolysis (tissue destruction before necropsy),

cannibalism, or management problems. TSCA

guidelines require at least 50-percent survival in

all groups, while FIFRA guidelines specify that

survival must not be less than 50 percent at 18

months for rats and 15 months for mice and not

less than 25 percent at 24 months for rats and 18

months for mice. IARC scientists suggest that a

study is not satisfactory if mortality is greater than

50 percent before week 104 (24 months) for rats

and 96 weeks (22 months) for mice.

All the guidelines describe the nature of the

necropsies that should be conducted after animals

die during the experiment or are sacrificed at the

end. In general, all the animals should be examined carefully, including gross visual examination

of a number of specified tissues. Instructions on

preserving tissues are given, and tissue portions

are prepared for microscopic examination to discover tumors and their types. The guidelines differ with regard to the extent of this microscopic

examination. In general, it is required for all observed gross lesions and for sections of major

body tissues. NCI guidelines require microscopic

examination of these tissues for all exposed and

control animals. The other guidelines allow for

less comprehensive microscopic examinations,

specifically, of all animals that died during the

study, all animals in the control group, and all

animals in the highest exposure group. Microscopic examination should also be conducted for

animals in lower exposure groups on the specific

organs (target organs) in which tumors were discovered in the highest exposure group, and in

some guidelines, on the lungs, livers, and kidneys

of all animals. Microscopic examination of animals in the lower exposure groups may also be

necessary if there are excessive early deaths or

other problems in the highest dose group.

A large part of the costs of long-term carcinogenicity bioassays owes to examining or reading the

large number of microscopic slides. For example,

EPA has estimated that a bioassay conducted to

meet the requirements of TSCA regulations will

generate about 40,000 slides, requiring about

three-quarters of a year of a pathologist’s time in

addition to the costs of technicians and materials. Because of these costs, the NTP Ad Hoc Panel

suggested that alternatives be considered to reduce

the burden of conducting microscopic pathology.

NTP has tried to implement such an approach to

reduce the pathology requirements. But when

using a reduced pathology system, NTP often

found it necessary to go back to the original tissues to obtain additional slides for diagnosis. Consequently, NTP has now returned to examining

all tissues at all dose levels. While the reduced

pathology system decreased the costs of pathology, it increased the time necessary to complete

the study (95,121).

Several of the guidelines also detail the qualifications necessary for principal study personnel.

NCI guidelines required that the study pathologist be board-certified and that histology technicians be supervised by a registered technician. The

NTP Statement of Work requires that the study

director have a doctorate in a relevant discipline,

that the pathologist have formal training and experience in animal pathology, and that histologists be registered with the relevant accrediting

organization. PMA guidelines specify only that

the pathologist should have expertise in laboratory animal pathology.

63-986 0 - 87 - 3
44

ANALYSIS OF AGENCY CARCINOGEN ASSESSMENT POLICIES

The following comparison will examine policies’ that have been issued by the major regulatory agencies:

●

●

●

●

●

●

●

EPA Interim Guidelines—EPA (1976) (ref.

293),

EPA Water Quality Criteria–EPA (1980)

(ref. 323),

EPA Standard Evaluation Procedure for Pesticides—FIFRA (1985) (ref. 328),

EPA Carcinogen Risk Assessment Guidelines–EPA (1986) (ref. 284),

CPSC Interim Carcinogen Policy —CPSC

(1978) (ref. 228),

OSHA Carcinogen Policy –OSHA (1980)

(ref. 276), and

FDA Sensitivity of Method Policy (proposed)–FDA SOM (1985) (ref. 246). -

There have also been several interagency collaborative efforts, and efforts by nonregulatory

bodies:

●

●

●

●

National Cancer Advisory Board, Subcommittee on Environmental Carcinogenesis—

NCAB (1977) (ref. 348),

Interagency Regulatory Liaison Group—

IRLG (1979) (ref. 347),

Office on Science and Technology Policy—

OSTP (1979) (ref. 23), and

Office on Science and Technology Policy—

C)STP (1985) (ref. 351).7

These policies were issued under a variety of

circumstances and are organized in several different ways. In some cases, they appear to have been

adopted as relatively informal statements of scientific understanding on how carcinogens might

be identified. In other cases, they are formally

adopted agency regulations, specifying how the

agency will identify carcinogens and attempting

to limit the kinds of arguments and evidence to

be considered in any specific regulatory proceeding. In between these two extremes, some docu-

‘See reference numbers in the following two bulleted lists for complete policy citations. Policies are only cited by year elsewhere in

this section.

‘This discussion does not cover one other policy that was prepared by the Committee to Coordinate Environmental and Related

Programs (CCERP) of the Department of Health and Human Services (232).

ments outline an agency’s standard procedures

and discuss problematic areas of interpretation,

often including the inference options the agency

will generally use. a

This chapter focuses on formal written policies,

with only limited attention to actual agency practices on carcinogen risk assessment. The policies

themselves will be referred to using agency acronyms and the year of the policy, for example,

OSHA (1980), OSTP (1985).

Definitions

Not all of these policies propose a formal definition of “carcinogen,” although in most cases the

text of the Policy outlines the various criteria and

considerations that will be used to identify and

classify carcinogens. In its simplest form, a carcinogen may be defined as a substance that causes

cancer (217). Two more complete definitions of

a carcinogen are those of OSHA (1980) and OSTP

(1985). OSHA gave the following definition of a

potential occupational carcinogen:

A

. . . any substance, or combination or mixture

of substances, which causes an increased incidence of benign and/or malignant neoplasms, or

a substantial decrease in the latency period between exposure and onset of neoplasms in humans or in one or more experimental mammalian

species as the result of any oral, respiratory or

dermal exposure, or any other exposure which

results in the induction of tumors at a site other

than the site of administration. This definition

also includes any substance which is metabolized

into one or more potential occupational carcinogens by mammals.

more recent definition is offered by OSTP:

. . . a substance which is capable under appropriate test conditions . . . of increasing the incidence of neoplasms (combining benign and

malignant when scientifically defensible) or decreasing the time it takes for them to develop.

OSTP (1985) added the qualification that, before

concluding that a chemical is carcinogenic, gen8

For another comparison of agency policies, see Rushefsky

(179,180).
45

eral principles in evaluating animal test results

should be followed (e.g., eliminating experimental

artifacts).

Qualitative Risk Assessment:

Hazard Identification

Use of Human Epidemiologic Data

Most policies declare that well-conducted positive epidemiologic studies provide conclusive evidence for carcinogenicity, The FIFRA (1984)

evaluation procedure did not discuss epidemiology at all, and FDA SOM (1985) treated it only

cursorily. In evaluating new pesticides and

residues of new animal drugs, it is not likely that

there will be relevant epidemiologic studies.

EPA (1986), IRLG (1979), and OSTP (1985) all

discuss in some detail several of the important

factors to consider in evaluating epidemiologic

studies, including the strength of association, level

of statistical significance, information on doseresponse relationships, biological plausibility,

temporal relationships, confounding factors and

bias, accuracy of exposure and cause-of-death

classifications, adequacy of followup, and

whether sufficient time has elapsed to allow for

latent effects.

One epidemiologic issue provoking special attention in many of these policies is the role to be

played by negative human studies in evaluating

chemical hazards. All Federal policies addressing

this issue state that negative human studies can

only set an upper bound on risk estimates. A negative study cannot prove the absence of a carcinogenic hazard. A negative study indicates, at most,

that the true risk is unlikely to exceed the specified upper bound. The magnitude of this upper

bound depends on the size of the study and the

background incidence of the cancer in question.

OSHA (1980) went even further than this, generally referring to negative studies as “nonpositive” studies. In characteristic fashion, OSHA

(1980) also set down explicit and stringent criteria

for when a “nonpositive” study would be acceptable evidence for an OSHA rulemaking. Such a

study will be considered only if:

1. the study involved at least 20 years of exposure and at least 30 years of observation

2.

3.

after initial exposure,

documented reasons are provided for predicting human cancer site(s) at which the

substance would induce cancer if it were carcinogenic in humans, and

the exposed group was large enough to detect a 50 percent excess risk at the predicted

sites.

To use a “nonpositive” study to set an upper limit

on risk, both of the first two criteria must be met

and, in addition, there must be reliable human

exposure data.

OSHA (1980) pointed out that there have been

negative studies for arsenic, benzene, coke oven

emissions, petroleum refinery emissions, and vinyl chloride, substances and mixtures now generally believed to be carcinogenic on the basis of

other epidemiologic studies. Even the epidemiologic evidence of the association between asbestos

exposure and lung cancer among nonsmokers was

“nonpositive” for a long time. Selikoff found no

excess of lung cancer among nonsmoking asbestos

workers for the first 30 years after exposure,

though 5 more years of followup demonstrated

a positive effect.

Use of Long-Term Animal Bioassay Data

All policies accept the use of animal data as

predictive for human beings. Explicitly or implicitly, all the policies acknowledge that substances shown to be carcinogenic in animals

should be presumed to present a carcinogenic hazard to humans.

An often-quoted statement on the value of animal data in assessing human risk is that of IARC.

Their principle is based on two points: that a number of chemicals were first identified as animal carcinogens, and then evidence confirmed carcinogenicity in humans. Second, all chemicals accepted

as human carcinogens that have been adequately

studied in animals are positive in at least one species. (See the discussion in ch. 4.) IARC concluded:

Although this association cannot establish that

all animal carcinogens also cause cancer in humans, nevertheless, in the absence of adequate

data on humans, it is biologically plausible and

prudent to regard agents for which there is suffi-
46

cient evidence of carcinogenicity in experimental

animals as if they presented a carcinogenic risk

to humans (99).

However, determining exactly what evidence will

be considered sufficient to demonstrate a substance to be an animal carcinogen is a little more

complex.

OTA identified the following major issues on

use of long-term animal bioassay data for hazard

●

●

●

●

●

●

●

●

determination in agency policies:

use of the maximum tolerated dose,

route of administration,

criteria for a valid negative study,

classification of tumors as benign or malignant and deciding which should count as evidence for carcinogenicity,

evaluation of certain problem tumor types

and commonly spontaneous tumors,

use of historical control data,

statistical evaluation, and

performance of overall qualitative evaluation.

Some of the agency policies also gave guidance

for the design of bioassays. These points have generally been covered in the earlier section on

testing.

Use of Maximum Tolerated Dose.-For reasons

of economics and practicality, long-term animal

bioassays are much too small to provide experimental data on the hazards of low exposures.

Therefore, to maximize the sensitivity of animal

bioassays for detecting carcinogenic effects,

agency guidelines for designing tests specify use

of the MTD. This position was also affirmed by

the Ad Hoc Panel convened by NTP to consider

issues in carcinogenicity testing (258).

In bioassays, the power of a study to detect a

tumor increase reliably depends on the number

of animals in each exposure group, spontaneous

incidence of the particular tumor increased, and

the magnitude of the increase. The probability of

missing an increase even though the substance is

truly carcinogenic (a false negative) is fairly high.

For example, with a standard bioassay design

using 50 animals per exposure level, the probability of not detecting an increased tumor incidence

from 1 percent in controls to 10 percent in the exposed group is 73 percent or nearly three-quarters

of the time (258).9

With one exception, all agency policies on interpreting test results accept positive test results

using the MTD. One policy (FIFRA 1984) raised

the concern that exposures at the MTD may represent a toxic insult qualitatively different than

those at much lower exposures. FDA (1985) indicated when test levels turn out to have exceeded

the MTD (after conducting the 2-year study), negative results do not remove suspicion about possible carcinogenicity. Several other policies address how to interpret positive results at levels that

exceed the MTD or show noncarcinogenic toxic

effects.

EPA (1986) suggested that studies be carefully

reviewed to determine whether the high exposure

levels induce effects that would not be seen at

lower levels. OSHA (1980) generally accepts positive results from high-dose testing. OSHA will entertain arguments that high doses are not relevant

to human exposures only if documentation shows

that:

1. at high doses the test animals produce

metabolizes that are produced only at high

doses,

2. these high-dose metabolizes are the ultimate

carcinogens and the ones produced at low

doses are not, and

3. the carcinogenic metabolizes are not produced

by humans exposed to low doses.

FDA SOM (1985) required “convincing evidence”

to rule out carcinogenic effects seen at exposures

above the MTD. OSTP (1979) suggested accepting these results only if the noncarcinogenic toxic

effects have not altered metabolism or immune

system responses in a way that could have caused

the carcinogenic effects, while OSTP (1985)

declares it is appropriate to consider animal test

results that use exposures exceeding human exposures although, as mentioned above, OSTP

(1985) also requires that possible organ damage

‘Using Fisher exact test with a one-sided significance level < 0.025.
47

and metabolic saturation (experimental artifacts

that may occur at high doses) be considered before concluding that a chemical is carcinogenic.

Thus, agency policies accept the use of highdose testing, but many policies raise concerns

about how to interpret test results at levels that

exceed the MTD. One difficulty in conducting

these tests is making a guess concerning the MTD

for a 2-year study based on the results from a 13-

week study. Sometimes the researchers estimate

poorly what the MTD will be. The result is that

the study is conducted with doses that are substantially above or below the MTD.

The decisions about how to use results from

these studies are a problem. The policies generally appear to reject use of negative results from

such studies, but differ in how to handle positive

results. FDA SOM (1985) accepted positive studies, even if the MTD was exceeded, “unless there

is convincing evidence to the contrary. ” OSHA

(1980) set a policy of entertaining arguments that

high-dose results are not relevant to humans only

if documented evidence is presented that shows

that the ultimate carcinogenic metabolizes are

produced only at high doses and not in humans

exposed at low doses.

Other policies are more restrictive in interpreting such studies. EPA (1986) asked for careful

review of studies at levels above the MTD to

determine if there was a response that does not

occur at lower exposures. FIFRA (1984) went further in arguing that use of the MTD was “interjecting biases of considerable importance” in

evaluating animal studies.

As will be discussed later in this chapter, there

are other difficulties in applying test results from

high doses in animals to predict human risk, even

using high doses that do not exceed the MTD.

Route of Administration. -In animal bioassays,

the substance under test may be administered in

any of several ways: it may be incorporated into

the animals’ diet, or into their drinking water; the

animals may inhale the substance as they breathe;

the substance may be dissolved in corn oil (or similar vehicle) and then administered through a feeding tube directly into their stomachs (in gavage);

or it may be injected or implanted in the animals

or painted onto their skin. Although it is desirable that the exposure route used in the animal

study be similar to human exposures, this is not

always possible. For example, some substances

when mixed with feed or water will alter the taste,

leading the animals to refuse to eat or drink

enough to receive the desired dose.

The two major issues of interpretation are these:

If an exposure route that differs from the human

route is used, are the results applicable to humans?

If tumors are found only in tests that use “unusual” administration routes (such as injection or

implantation) or the tumors are found only at the

site of administration, are these results applicable to humans?

One view the policies express is that if the resultant tumors are found in organs or tissues distant

from the site of application, then the substance

should be considered a carcinogen, irrespective

of the route of exposure. EPA (1980), OSHA

(1980), and IRLG (1979) clearly express this view.

On the other hand, tumors found only at the site

of administration or by unusual methods may

“raise the possibility” of carcinogenicity (NCAB

1977) or might be used as “concordant evidence”

(OSHA 1980). Other policies caution that these

results merit additional evaluation in assessing

their human relevance (EPA 1984, CPSC 1978)

or suggest that more testing is needed to resolve

safety concerns (FDA SOM 1985). OSHA (1980)

treated as indicative of carcinogenicity any contact tumors (those occurring at the site of exposure), from oral, respiratory, and dermal exposure routes and noncontact site tumors (those

found at sites away from the exposure site),

regardless of the route of exposure. OSHA (1980)

will consider arguments that a tumor response

only at the site of administration is not predictive of human hazard if: 1) the exposure route is

not oral, respiratory, or dermal (i. e., is through

injection or implantation); and 2) the tumor induction is related to physical configuration or formulation of material and not to its chemical properties.
48

Criteria for Valid Negative Study .—Two of the

policies provide criteria that must be satisfied for

an animal study to be considered a negative study.

(As discussed above, some of the test protocols

also provide minimum standards for negative

studies. ) For the IRLG, negative test results can

only be considered evidence of no effect when

“minimum requirements have been met. ” “Accepted procedures” include: a) the observation of

all animals in the study . . . until their spontaneous death, b) the sacrifice of animals that show

clinical signs of severe illness or impending

death . . ., and c) terminal sacrifice at a scheduled date near the end of the lifespan (e.g., after

24 months on test). None of the other policies provide criteria for a valid negative animal study,

although, as discussed below, many of these policies do specify the weight to be given to “negative” studies.

EPA’s CAG guidelines (1986) do not specify

minimum test design requirements, but provide

that a substance will be classified in the “no evidence” category if there is no tumor increase in

“at least two well-designed and well-conducted

animal studies of adequate power and dose in

different species.”

Use of Data on Benign and Malignant Tumors.

—When diagnosing cancer in a human patient,

microscopic examination of tumor tissue yields

a classification of the tumor as benign or malignant. Cancer is a disease of malignant tumors,

that is, ones that have the potential to invade

other tissues and spread throughout the body. The

cells of benign tumors, on the other hand, remain

together and do not invade other parts of the

body. The clinician can then formulate a prognosis and develop a therapy based on whether the

tumor is benign; malignant, having the potential

to spread, but localized; or already widespread.

Benign tumors may still be of concern, however,

because if they develop in vital organs (e.g., the

brain), they can cause serious disability and death.

This classification is also used when examining animals exposed during a bioassay. While

there are difficulties in the precise classification

of some tumors, 10 the more general Controversy

1NCAB (1977), FIFRA (l984), and OSTP (1985) pointed to the

lack of standard nomenclature for classifying tumor types and the

need for professional judgment in examining tissue slides.

concerns how to count the tumors diagnosed as

“benign.” If there is an increase in benign tumors

in the exposed groups compared to the control

group, with no increase in the number of malignant tumors, should that increase in benign tumors be sufficient to classify a substance as a carcinogen? If there is no statistically significant

increase in the frequency of malignant tumors, but

benign and malignant tumors together increase,

should that serve to classify a substance as a carcinogen?

Most of the policies have taken the position that

it is appropriate to count both benign and malignant tumors when evaluating the carcinogenicity of a substance, although EPA and NTP policies now provide that benign tumors will not be

grouped with malignant tumors when they are of

a type that is not known to progress to a malignant stage. This principle of grouping tumors

based on their potential for progression appears

to be gaining general acceptance. The burden,

however, is to demonstrate that progression is not

likely. In the absence of such evidence, the benign tumors will be grouped with malignant ones.

As an example of an early policy, NCAB (1977)

argued that because compounds that induce benign tumors frequently also induce malignant

ones, that because benign tumors may represent

a stage in transformation to malignancy, and that

because benign tumors may themselves endanger

health, “if a substance is found to induce benign

neoplasms in experimental animals it should be

considered a potential human health hazard which

requires further evaluation. ” If the increase in

malignant tumors is of questionable significance,

the NCAB (1977) policy provided that a parallel

increase in benign tumors in the same tissue adds

weight to evidence for carcinogenicity. CPSC

(1978), IRLG (1979), OSHA (1980), and FDA

SOM (1985) all provide for grouping benign and

malignant tumors together. EPA (1976) and EPA

(1986) provided for combining benign and malignant tumors, unless the benign tumors are not

considered to have the potential to progress to

malignancy. FIFRA (1984) cited the 1984 proposal

of the EPA (1986) guidelines and also includes a

list, prepared for the NTP Ad Hoc Panel, of specific tumor types that should and should not be

combined. OSTP (1979) apparently dropped a
49

discussion of benign and malignant tumors in their

final document because a “wide range of opinion”

had been expressed, making it “clear that no consensus exists on this issue. ”

For cases in which the animal response consists

of only “benign” tumors, EPA (1976) and EPA

(1986) would classify an increased incidence of benign tumors alone as only “limited” evidence of

carcinogenicity. OSHA (1980) did allow for the

possibility of a benign-tumor-only response, although it required a substantial amount of proof

that this response is truly limited to benign tumors

and that the tumors will not progress to malignancy,

For evaluating its bioassays, NTP considers

chemically induced benign tumors to be an “important toxicological indicator of a chemical’s carcinogenic potential in rodents, ” and includes these

findings in its evaluations. A substantially increased incidence of benign tumors alone may

serve to place an experimental result in the category of clear evidence for carcinogenicity category, as discussed below.

Although the weight to be placed on benign

tumors remains controversial, the fact remains

that very few chemicals testing positive in

NCI/NTP studies induced only benign neoplasms.

Of 113 chemicals studied by the NTP and reviewed by the NTP Peer Review Panel at the time

of the analysis, 56 were found to have evidence

of carcinogenicity in rodents. Of these, only four

(7 percent) were based entirely on the finding of

benign neoplasia. Moreover, none of these four

were placed in the category of “clear evidence. ”

Of the 56 chemicals, 20 were carcinogenic in all

experiments (17 in all 4 experiments, 1 in 3 of 3

experiments, and 2 in 2 of 2 experiments). Of these

20, all caused malignant neoplasms (92).

Evaluation of Certain Problem Tumor Types,

Common Spontaneous Tumors, and Historical

Control Data.—Another difficulty in evaluating

bioassay results arises when an increase in the frequency of relatively common, “spontaneous”

tumors is found. “Spontaneous” tumors are ones

that arise, generally for unknown reasons, in animals that are not being deliberately exposed to

a carcinogenic agent. The difficulty in interpretation occurs because the incidence of some spontaneous tumors is relatively high and variable.

—

This variability can create an especially problematic situation for evaluation when the control

group in a particular bioassay happens to have

had a spontaneous tumor incidence that is on the

low side of the range for the particular species or

strain of laboratory animal. (This may occur simply as a result of random variations among groups

of animals: some will be above average, some below average in the incidence of tumors. ) For a particular bioassay, the exposed groups may then

have a tumor incidence that is similar to what

could be expected for purely spontaneous tumors,

but there would appear to be a significant excess

just because the control group had an abnormally

low incidence. In addition, background frequency

may in some cases be affected by the animals’ diet

and metabolic state. On the other hand, if the

study has been conducted properly, the animals

will have been assigned randomly to treatment

and control groups. A control group with an abnormally low incidence would be accompanied

by exposed groups that would be expected to have

had a similar incidence if they had not been

exposed.

Historical control data consist of information

on the incidence of tumors in groups of control

animals of particular species and strains within

a given laboratory or from a particular source of

animals. Historical control data can be useful in

two circumstances:

1. judging the likelihood that the difference in

tumor incidence between the exposed and

concurrent control group (the animals used

during the actual study) can be explained as

random variations within an unexposed population of animals; and

2. judging whether a rare tumor maybe of concern, even though the comparison between

exposed and control groups has low statistical power because there are very few cases.

Care must be taken when using historical control data because spontaneous tumor incidence

can change over time as a result of genetic changes

in the animal population over generations or

changes in pathology and tumor diagnosis. In

addition, there may be differences of opinion

among the pathologists who examined the different sets of animals. Because concurrent controls
50

have been treated to the same conditions, except

for chemical exposure, as the exposed group, and

have been examined by the same pathologists,

they are the best source of information on the

spontaneous tumor incidence in the group of animals being studied.

In their policies, OSHA (1980) and CPSC (1978)

simply declared that a significant increase in spontaneous tumors would serve to identify carcinogens. NCAB (1977) concluded that an increase in

spontaneous tumors would “raise the possibility”

that a substance was carcinogenic, and IRLG

(1979) urged caution in interpreting bioassay

results when the observed increase in a spontaneous tumor type is within the range observed in

historical controls from the same colony of

animals.

OSTP (1985) acknowledged the problems of

evaluating increases in spontaneous tumors, emphasized the need to consider other biological evidence, and suggested that historical controls can

aid in evaluation, although “care should be exercised when combining different control groups. ”

FIFRA (1984) suggested that while the occurrence of spontaneous tumors “complicates” evaluation, “judicious use” of historical control data

can be of assistance, although it should not substitute for concurrent control data. However, in

an example given in the text, the authors of FIFRA

(1984) discounted an apparent tumor excess because the incidence in the exposed group was within the range found in historical controls. FIFRA

(1984) also described how historical control data

could be used for interpreting the observation of

rare tumors, while it cautioned that underlying

spontaneous frequency can change, depending,

for example, on changes in pathology technique.

According to IRLG (1979), the occurrence of

rare tumors raises suspicion and is worthy of careful review, but this occurrence by itself is “not

necessarily evidence” of carcinogenicity without

additional supporting evidence.

Because an increase in the occurrence of mouse

liver tumors is a subject of continuing controversy, some policies have special provisions for

dealing with this result. According to EPA (1986),

a bioassay that shows an excess only in mouse

liver tumors should be considered “sufficient” evidence of carcinogenicity when other conditions

for classification of “sufficient” evidence occur.

Classification of evidence could be downgraded

to “limited,” however, if a number of factors

among the following are observed:

●

●

●

●

●

●

the liver tumors occur only in the highest

dose group or only at the end of the study,

there is no substantial dose-related increase

in proportion of tumors that are malignant,

the tumors that occur are predominantly

benign,

there is no dose-related shortening of the time

to tumor appearance,

short-term tests are negative, or

excess tumors occur only in one sex.

Statistical Evaluation. —Only a few of the policies actually devote any substantial discussion to

the topic of statistical analysis of bioassay results.

OSHA (1980), EPA (1986), and OSTP (1985)

tated that such analyses shall be performed.

OSHA (1980) did provide that these analyses

would not be used exclusively to evaluate evidence for carcinogenicity. EPA (1986) provided,

on the other hand, that evidence for carcinogenicity should be based on statistically significant

response in specific organs or tissues, although the

weight given to level of significance and other information is “a matter of overall scientific judgmerit. ” The policies have not specified the level

of statistical significance to be used in evaluation.

Overall Evaluation of Bioassay Results.—Some

of the policies provide a list of some general principles for overall evaluation of bioassay results.

EPA (1986) stated that the strength of positive evidence increases with:

●

●

●

●

●

an increase in number of tissue sites affected;

increase in number of species, strains, and

sexes showing response;

“occurrence of clear-cut dose-response relationships” and high level of statistical significance of tumors in treated compared to control animals;

dose-related shortening of time to tumor

occurrence or time to death with tumor; and

dose-related increase in proportion of malignant tumors.
51

OSTP (1985) listed several factors that increase

confidence in the conclusion that a substance is

a carcinogen. These include:

●

●

●

●

●

an observed dose-response relationship,

a marked increase in tumor incidence in treatment groups,

tumors being found at multiple sites,

significant reduction in latent period, and

information comparing the neoplastic stages

of tumors in treatment and control groups.

In addition, information on preneoplastic lesions,

target organ effects in prechronic studies, and

chemical activity at physiological, cellular, and

molecular levels may help.

But OSTP (1985) added a caution:

. . . the carcinogenic effects of agents maybe influenced by non-physiological responses (such as

extensive organ damage, radical disruption of

hormonal function, saturation of metabolic pathways, formation of stones in the urinary tract,

saturation of DNA repair with a functional loss

of the system) induced in the model systems.

Tests that produce these responses need to be

evaluated for human relevance, according to

OSTP (1985). While there has always been concern that high-dose testing might not be relevant

to human exposures, the OSTP (1985) caution

represents a more explicit discussion of these potential problems than had been seen in most earlier

policies.

Use of Short-term Tests and StructureActivity Relationships

While none of the agency policies provided for

using positive short-term test results as the sole

basis for identifying or regulating carcinogens,

they all indicated that such test results may be

used either as supporting information (EPA 1980,

EPA 1986, OSHA 1980, IRLG 1979, OSTP 1985)

or as an indication that further testing may be

warranted (CPSC 1978, NCAB 1977, OSTP

1979).

Few of the policies directly discussed use of

structure-activity relationships (SARS) to identify

carcinogens. Of those that do, none will use SARS

as the sole basis for such identification, although

IRLG (1979) states they might be used as corroborative evidence along with other data, or in

the absence of other data, as limited, suggestive

evidence. EPA (1980) states that SARs will not

be used as the sole basis for quantitative risk

assessments, while CPSC (1978) suggests that if

related chemicals are carcinogenic, the chemical

in question should be tested prior to being used

in consumer products.

Evaluating Conflicting Data

There are major issues in evaluating substances

for carcinogenicity when the evidence is mixed,

such as both positive and negative results in animal bioassays, or negative data in human studies

and positive animal data. Many of the policies

have come to conclusions about what to do in

these situations, and provide guidance for the

overall qualitative evaluation.

Conflicting Animal Data.—Animal evidence

may differ in two ways: it may be positive and

negative studies in different species, or positive

and negative studies in the same species. Agency

policies generally hold that positive results in one

species outweigh negative results in another.

Thus, in theory, the policies imply that agencies

can regulate chemicals based on positive results

in a single species. This principle, that positive

results supersede negative results, may be extended to cover not just conflicts between results

in different species, but also conflicting results in

different strains of the same species or between

sexes. Of course, arguments will still occur over

what constitutes convincing positive evidence.

Conflicting positive and negative results in the

same species will, in general, provoke a caseby-case evaluation. For example, EPA (1986)

provided:

Positive responses in one species/strain/sex are

not generally negated by negative results in other

species/strains/sexes. Replicate negative studies

that are essentially identical in all other respects

to a positive study may indicate that the positive results are spurious.

Conflicting Animal and Human Data.—Similarly, the policies generally provide that positive

animal data will outweigh negative human data.

OSTP (1979) points out that limitations in the

power of human epidemiologic investigations to

detect an effect can often explain the apparent dis-
52

crepancy between positive animal data and negative human data. As noted elsewhere, EPA

(1980) and IRLG (1979) provide that in these situations the negative human studies can be used

to set an upper bound on the estimate of human

risk.

Quantitative Risk Assessment:

Dose-Response Determination

The NAS committee divided the more quantitative aspects of risk assessment into doseresponse determination, exposure estimation, and

risk characterization. Quantitative estimation has

been a particularly vexing area because of the need

to make a series of often untestable assumptions

to perform quantitative extrapolation from animal to human cases, the inadequacy of historical

information from epidemiologic studies, and a frequent lack of data on current human exposures.

During the 1970s, many argued that quantitative

risk assessment was far too imprecise for use by

regulatory agencies except for the relative ranking of different hazards for setting priorities.

OSHA (1980) in fact adopted this position in its

cancer policy, although because of court interpretations of its regulatory authority, OSHA now

conducts quantitative risk assessments.

Long-term animal bioassays provide information relating the dose administered to the animals

(the exposures) to the proportion of animals that

are diagnosed with tumors. In these bioassays, exposure levels are deliberately set at high levels to

maximize the probability of detecting a carcinogenic effect.

Information from epidemiologic studies may be

used to relate some measure of exposure with the

proportion of people incurring cancer, although

there are often significant inaccuracies in exposure

estimates made many years ago. For epidemiologic studies, the population examined is often a

group of workers who were exposed to relatively

high levels, often much higher than the levels

workers are currently exposed to or that the public

may be exposed to.

In many ways, the problems of extrapolating

from effects of high doses to those of low doses

differ based on whether one is using epidemiologic data or animal data. For example, an epidemiologic study may have examined the incidence of lung cancer among workers exposed to

relatively high levels of arsenic inside a plant. Extrapolating from those exposures to the lower exposures found among community residents outside the plant poses difficulties, but the magnitude

of the range from high worker exposure to lower

ambient environmental exposure is less than that

encountered when extrapolating from animal

study results. As mentioned earlier, the highest

exposed animals are to be exposed at the MTD.

The exposures in human study populations are

high compared to general environmental exposures, but are not at levels approaching the

MTD. Of course, for regulating worker exposures, frequently the exposure levels for the

study population are close to those found in workplaces that are to be regulated.

When using either animal or human data, the

first issue is to extrapolate from the estimated

probability of harm at these higher exposure levels

to estimate what the probability of harm is at the

lower exposure levels of interest. This high- to

low-dose extrapolation is often very uncertain and

controversial because there are usually few observed data on health outcomes at the lower

levels.

This problem is most severe in the case of animal data because of the use of the MTD in those

studies. The dose levels that the animals are exposed to are often several orders of magnitude

greater than exposures that most people experience in the general environment .11

Risk assessors using epidemiologic data of exposed worker groups must also extrapolate from

relatively high exposures to low exposures. Past

exposures, before the agent’s toxic effects were

recognized or before the beginning of concerted

public and private efforts to reduce workplace

hazards, were often much higher than current exposures, and nearly always much higher than proposed new exposure limits. For example, workers exposed to benzene during the 1950s and 1960s

at levels substantially above the current OSHA

11 Orders of magnitude refer to differences that can be expressed

in powers of 10. Thus the difference between 10 and 100 is one order of magnitude, while the difference between 10 and 1,000 is two

orders of magnitude.
53

standard of 10 ppm incurred a significantly increased risk of leukemia. But how large is the risk

of leukemia among workers currently exposed below 10 ppm?12

Unfortunately, there are very often few data

on historical exposure levels because quantitative

industrial hygiene measurements may never have

been taken. In these cases, the risk assessors must

make guesses about what the exposure levels

were.

The relationship between dose (or exposure)

and biological response (in this case the induction

of cancer) is one of the most fundamental in the

fields of toxicology and epidemiology. If data on

exposures and responses are available, they may

be plotted on a graph. The line joining these plotted points is called a dose-response curve. Generally, the dose-response curve has a positive

slope, that is, the greater the dose, the larger the

response.

Even so, the dose-response curve may have several different shapes, ranging from a straight line

to differently shaped curves. Figure 2-1 shows several possible dose-response curves. In an ideal

world, dose-response assessment would ascertain

the shape of the curve and thus make estimates

of what human risk is likely to be. In this ideal

world, there would be data on the response in the

range of human exposures, and there would be

enough data points at different levels to distinguish between different possible dose-response

curves. Alas, in the real world, the data from animals usually represent dose levels substantially

higher than the range of human exposure, often

several orders of magnitude higher.

A number of methods have been proposed for

extrapolating from high to low doses. They range

from the simple technique of drawing a straight

line on a graph to sophisticated computer programs that fit the available data to develop a

mathematical equation relating exposure to response. As discussed below, the Federal agencies

have adopted linear no-threshold models, which,

while allowing for nonlinear dose-response curves

at higher exposures, extrapolate to low doses using

an assumption of low-dose linearity.

12 See ref. 172 for a recent study of the dose-response for benzene.

Figure 2-1 .—A Stylized Dose-Response Curve and

Some- Extrapolated Curves

90

10

0

1/8 1/4 1/2 I D 2 D 3 D

D D D

Dose of test chemical

aExcess tumor incidence (percent) is defined as

tumors in exposed population – tumors in control Population x 100

number of exposed population number of exposed population

a slgmoid dose-response curve; infralinear between O and P,

-.–- linear extrapolation

— — . supralinear extrapolation

------ line projected to a threshold

SOURCE: U.S. Congress, Office of Technology Assessment, Assessment of Technologies for Determining Cancer Risks from the .Environment (Springfield, VA: National Technical Information Service, June 1981).

Agency Policies on Dose= Response

Assessment

The different policies of the Federal agencies

contain various degrees of discussion concerning

some of the problematic areas of quantitative risk

estimation. These policies include a series of assumptions about how to estimate human risk

based on animal data. Some of the assumptions

discussed in this section apply only to risk assessments based on animal data (choice of animal species and species conversion factors), while the

others apply to use of both human and animal

data.

Do Thresholds Exist?

The first issue in dose-response determination

concerns whether there might be a “no effects”

or “safe” level of exposure to carcinogens. This
54

particular issue has generated intense regulatory

debates.

For noncarcinogenic toxic agents, toxicologists

have generally believed that no-effect thresholds

could be determined. To do so, several groups of

animals would be exposed at different levels to

a toxic agent. At the higher exposures, most of

the animals might suffer toxic effects, while at the

lowest levels none of the animals would show such

effects. The researcher would then determine

which of the various exposure levels was associated with no toxic effects and declare that to be

a NOEL or a “no observed adverse effects level”

(NOAEL). To estimate “safe” human exposures,

the highest NOEL or NOAEL would be divided

by a safety factor, often by 10 or 100. The underlying premises were that human response was similar to that in the tested animals, that humans had

some ability to detoxify the harmful agent or recover from its effects, and that the safety factor

would provide sufficient protection from incorrect guesses about the degree of toxicity.

However, for carcinogenic effects the general

belief in the scientific community is that it is not

possible to determine a no-effect threshold for carcinogens. This belief is based on observations, experimental limitations, and theoretical considerations.

Dose-response data from many epidemiologic

and toxicologic studies of carcinogens fit mathematical models that are linear without an apparent threshold. Also, because of experimental limitations inherent in the size of bioassays typically

used, it is not possible to demonstrate conclusively

the existence of a no-effect threshold. This is especially true for risk levels of interest to regulators,

which are much smaller than those detectable in

these studies.

Certain theoretical considerations about cancer causation also imply the absence of no-effect

thresholds. Cancer is a disease of self-replicating

cells. Tumors can begin from a single cell, the

DNA of which has been damaged by a small

amount of a carcinogenic chemical. Unless that

damage is repaired, the genetic material of the

cell’s “daughters” will have been altered. These

daughter cells are then irreversibly “initiated” and

may eventually develop into a tumor. Various cellular repair processes do exist, but these repair

processes will lead to a no-effect threshold only

if their efficiency is 100 percent.

Moreover, even if thresholds for individuals

could be determined, genetic differences among

people would make it difficult to demonstrate a

no-effect threshold for a population. Finally, if

exposure to a carcinogenic agent is contributing

to the background incidence of cancer, the additional effect of the new carcinogen is approximately linear at low doses, without a no-effect

threshold.

On the other hand, there are data from epidemiologic and toxicologic studies that are curvilinear. Some scientists interpret these data as revealing possible thresholds. Some scientists also

believe that a threshold may exist if the carcinogen acts through an indirect mechanism, although

it is currently difficult to distinguish among carcinogens based on mechanism. In addition, if the

carcinogen contributes to the background of cancer, the additional effects will be linear and would

not show a threshold. Finally, even if carcinogens

lack a theoretical no-effects threshold, many believe that at some finite exposure level the additional risk is so low that it may be regarded, for

practical purposes, as safe. In this case, the carcinogen might be considered to have a practical

threshold.

For policy reasons, in addition to these scientific considerations, the agencies have generally

assumed that carcinogenic chemicals lack no-effect

thresholds. This reflects the agency’s desire to be

conservative in assessing risk, that is, to err on

the side of safety in protecting public health. Most

of the agency policies endorse the view that noeffects threshold levels do not exist for carcinogens. EPA (1980) presents this view:

Because methods do not now exist to establish the presence of a threshold for carcinogenic

effects, EPA’s policy is that there is no scientific

basis for estimating “safe” levels for carcinogens.

The criteria for carcinogens, therefore, state that

the recommended concentration for maximum

protection of human health is zero.

EPA (1986), CPSC (1978), OSHA (1980), FDA

(1985), IRLG (1979), and OSTP (1985) also set

forth the position that there is no safe exposure
55

level for carcinogens. EPA (1976) stated that the

linear model derived from study of radiation effects is also applicable to chemical carcinogens,

but added that the costs of prohibiting exposures

to some chemicals might be socially unacceptable.

Two of the policies, however, did not strongly

endorse the no safe threshold principle: OSTP

(1979) and FIFRA (1984), OSTP took no stand

on the issue, citing disagreement within the scientific community. FIFRA argued that the noeffect threshold concept is contrary to the toxicologic principles for other kinds of toxicity, suggests that this concept has inhibited scientific discussion in this field, and provides that if an EPA

evaluator believes a threshold exists, this fact

should be stated along with its rationale.

Mathematical Models for Fitting Data and

Extrapolating From High to Low Doses

Beyond the issue of whether safe thresholds

might be discoverable, the agencies have issued

some guidance concerning the techniques that will

be used to describe, in mathematical terms, the

dose-response relationship. This process is important because carcinogens vary a great deal—by

a factor of more than 10 million—in their potency

(70). Quantitative dose-response estimation is designed to produce estimates of carcinogenic potency, which can then be used to estimate the

degree of human risk associated with a given exposure level or the exposure level that corresponds

to a preselected level of human risk, for example, what exposure would lead to an increased risk

of 1 in 1 million? Information on the degree of

risk for given exposure levels can be further combined with information on exposure levels to estimate the number of cases occurring or expected

to occur in a population. These estimates could

then be used to decide on a particular regulatory

action.

The basic issue at this step in risk assessment

is to develop estimates of response rates at low

exposure levels using dose-response information

from the generally much higher doses of animal

bioassays or epidemiologic studies. Put another

way, the problem involves extrapolating from the

high-dose region of the dose-response curve where

animal tumor rates are in the range of 5 to 50 percent to the low-dose region corresponding to an

estimated human incidence range of between 1

case for every 100,000 people (10-5) to 1 case

for every 100 million people (10-8). ’3

A variety of mathematical models have been

proposed for this analytic step. These models fall

into three basic types: mechanistic models, tolerance distribution models, and time-to-tumor

models (351). The major ones used by the agencies include the multistage, one-hit, multihit, logit,

probit, and Weibull models.

Animal bioassays produce only a few points on

the dose-response curve: the tumor incidence for

two or three exposure levels and the control

group. A major difficulty in risk assessment is that

many of the mathematical models can fit these

two or three data points equally well, yet differ

by orders of magnitude in the corresponding estimates of human risk at low doses. Figure 2-2 illustrates several possible dose-response curves in

the low dose region. All of these curves fit the actual experimental data reasonably well, but the

models underlying them utilize different assumptions about the nature of the biological processes

that may be involved.

Choosing among these competing models involves questions of risk assessment policy. The

major issues include crucial assumptions concerning whether there might be a no-effect threshold,

whether the risk of exposure adds to the background cancer rate, whether the dose-response

curve at low doses is linear, and the precise mathematical techniques for the calculation algorithm.

As a rule, the agency policies endorse models

that assume the absence of no-effect thresholds

and that the low-dose portion of the dose-response

curve is linear. The assumption of linearity is

based on several considerations and is generally

thought to be conservative in the sense that it is

unlikely to understate the true risk. Recent research, however, indicates that this assumption

is not always true. In these cases, the doselsFor environmen t] exposures, there is no consensus on what level

of risk might clearly be considered “desirable,” “acceptable,” or “unacceptable, ” but agencies often act to regulate exposures that pose

a cancer risk greater than 1 death for every million people exposed

(or a risk of 1O-’).
56

Figure 2=2.—Possible Types of Dose-Response Curves

in the Low-Dose Region

0.01 0.1 1.0 10.0

Dose (μg/week)

SOURCE: National Academy of Sciences/National Research Council, Risk Assessment in the Federal Government: Managing the Process (Washington, DC: National Academy Press, 1963).

response curve may be supralinear and the use

of linear models may actually underestimate the

true risk (13). On the use of models, OSTP (1985)

states:

No single mathematical procedure is recognized as the most appropriate for low-dose extrapolation in carcinogenesis. When relevant biological evidence on mechanism of action (e.g.,

pharmacokinetics, target organ dose) exists, the

models or procedures employed should be consistent with the evidence. However, when data

and information are limited, and when much uncertain y exists regarding the mechanisms of carcinogenic action, models or procedures which incorporate low-dose linearity are preferred when

compatible with the limited information.

Over time the agencies have become more convinced that quantitative extrapolation is possible

and useful. NCAB (1977) emphasized the uncertainties of extrapolating based on animal data.

OSHA (1980) rejected an approach of setting regulatory standards based on quantitative risk

assessment. On the other hand, EPA, with the formation of CAG in the mid-1970s, began applying quantitative extrapolation and the agency has

now built up an extensive background in risk

assessment.

One important change in the late 1970s was

EPA’s shift away from the “one-hit” model to the

linearized multistage model developed by Kenneth

Crump (discussed in EPA 1980). While this model

is able to fit dose-response curves in the high-dose

region that are very curvilinear, the upper confidence limit of this model is effectively linear in

the low-dose region. This model was chosen because it was compatible with the multistage theory of carcinogenesis and because it uses all the

data from most animal experiments (123).

Some of the policies also indicated that a variety of models should be used in any particular

case (EPA 1976, OSTP 1985). The use of several

different plausible models allows the risk assessor to characterize the potential uncertainty that

is related to the choice of model. Some policies,

in particular OSTP (1985) and EPA (1986), emphasized that selection of the extrapolation model

must be chosen case by case. The chosen model

should be the one that has the most correspondence with other evidence which relates to the expected mechanism of action and to the biological activity of the chemical in question. The

selection should also be based on statistical considerations. In both of these policies, however,

there was a preference for models which incorporate an assumption of low-dose linearity. FDA

(1985), in contrast, stated that using a variety of

models is not likely to provide useful information.

Should Dose-Response Estimates Be Upper

Confidence Limits or the Maximum

Likelihood Estimate?

There has been some debate on which of two

different risk estimates-maximum likelihood estimates or upper confidence limits—should be emphasized in risk assessments. For a given model,

a maximum likelihood estimate is the estimated

risk at low doses that corresponds to the maximum likelihood curve, which is defined as the

mathematical curve that best fits the given highdose data. The upper confidence limit (often designated as the 95-percent confidence limit), for a
57

given model, is calculated under certain assumptions about the dose-response curve and is linear

in the low-dose region.

For example, the results of a bioassay for exposures at 100 and 200 ppm can be fed into the

computer. The program generates a risk estimate

for exposures at 0.1 ppm. The maximum likelihood estimate might be 1 chance in 10,000 or 1

x 10-4, while the upper confidence limit might

be 1 chance in 100 or 1 X 10

-2

.

The estimated risk at the upper confidence limit

will be higher than that for the maximum likelihood estimate. For certain dose-response data, the

difference will not be important. For other data,

the differences may be large. Of course, if the

underlying model is wrong, then both the maximum likelihood estimate and upper confidence

limit will also be wrong.

Because the upper confidence limit is forced to

be linear in the low-dose region, it allows for the

dominant view that carcinogens lack no-effect

thresholds and have dose-response curves that are

linear at low doses. It is usually stated that the

true risk is unlikely to exceed the upper confidence

limit, and it is possible that the true risk is actually less. Although this is the case for most bioassay data, for some data sets this is not always

true.

Some argue that the maximum likelihood estimate is the “best estimate” for a given model and

ought to be used in preference to the upper confidence limit, which is possibly too high and

thought to represent unnecessary conservatism.14

In fact, the maximum likelihood estimate maybe

misnamed. It is the extrapolated risk estimate for

a particular dose on the maximum likelihood

curve, which, under certain assumptions about

the mathematical form of the dose-response curve,

is the curve that most closely fits the actual experimental data.

But it is possible, with certain high-dose animal data, to develop a maximum likelihood estimate for the low doses of regulatory interest that

does not have a linear term and would thus not

l~Because different models give different estimates, the best estimate depends on the model selected.

exhibit low-dose linearity. Because, for reasons

discussed above, it is generally presumed that the

dose-response curve for carcinogens is linear at

low doses, the maximum likelihood estimate in

these cases would systematically understate the

“most likely” risk based on our understanding of

cancer causation. Moreover, small fluctuations in

the underlying data at high doses in the bioassay

can dramatically change the maximum likelihood

estimate at the low doses of interest. The upper

confidence limit is a more stable number. Finally,

because in most cases the true risk is not likely

to exceed the upper confidence limit, a regulation

based on this estimate will be sufficiently protective. Thus, the estimates based on upper confidence limits are used not only to be conservative

in assessing risk, but because a dose-response curve

that is linear in the low-dose region is plausible

on biological grounds.

Only two of the policies explicitly chose between the maximum likelihood estimate and the

upper confidence limit. Both of these are in discussions prepared by CAG. For EPA’s water quality criteria documents (323), the discussion supports the adoption of the linearized multistage

procedure developed by Kenneth Crump. Although

EPA’s CAG still uses the upper confidence limit,

EPA (1986) seems to respond to critics of the

upper confidence limit with a different view:

Such an estimate [based on the upper confidence limit] . . . does not necessarily give a realistic prediction of the risk. The true value of the

risk is unknown, and maybe as low as zero. The

range of risks, defined by the upper limit given

by the chosen model and the lower limit which

may be as low as zero, should be explicitly

stated.

EPA (1986) argued that current data and procedures do not allow calculations of “best estimates, ” but promises to use them if they become

available, most likely “when human data are

available and when exposures are in the dose

range of the data. ”

Choice of Data: Using the

Most Sensitive Species

If data on carcinogenic response are available

from more than one animal study or from both

animal and human studies, which of these data
58

sets should be used? The general principle in the

agency policies is to use the data from the most

sensitive species, that is, the study showing the

highest response for a given exposure level, provided the study is of acceptable quality (EPA

1980, OSHA 1980, IRLG 1979).15 The general rationale is that little is known about the relative

sensitivities of different species and in the absence

of evidence on the effects of a chemical in human

beings, it is not possible to know human sensitivity. Because it is possible that humans are in

fact the most sensitive species, the approach taken

is to use data for the species, strain, and sex that

is most sensitive, and not to reduce the risk estimates by combining data from a less sensitive species, strain, and sex.

EPA (1986) suggests use of animal data from

a species that responds most like humans, if information on this correlation exists. In the more

likely event that it does not exist, then the policy

suggests use of all biologically and statistically

acceptable data from all animal studies to identify a range of risk estimates. However, emphasis is to be placed on results from the “animal

studies showing the greatest sensitivity . . . with

due regard to biological and statistical considerations. ” When human and animal exposure routes

differ, the policy states that the risk assessment

should consider uncertainties about doses delivered to target organs and outline the assumptions

used.

Species Conversion Factors

The second important mathematical step in

dose-response assessment is estimating human

doses or exposures equivalent to those used in the

animal studies (converting “from mouse to man”).

There are several different ways this can be done:

using the ratio of body weights, the ratio of body

surface areas, daily or lifetime doses; or by assuming equivalence in terms of exposure concentrations in food, air, or water. Depending on the

method and whether rat or mouse data are being

used, the resulting risk estimates can vary by up

to a factor of 40 (217).

15If however, human data are also available, those data may be

used to set an upper limit on the risk estimates, as discussed above.

The two most debated methods for cross-species scaling use the ratio of body weights and the

ratio of body surface areas.16 The assumption that

equivalent doses may be calculated using body

surface areas was based on studies of the effects

of certain drugs in different species. Studies of

some other drugs and chemicals show effects that

are proportional to the ratio of body weights. The

choice of the body weight conversion (using mg/

kg/day), will lead to risk estimates that are onefifth (using rat data) to one-twelfth (using mouse

data) of those developed using the surface area

conversion (mg/m3

). Thus the risk estimates

scaled using body surface area will indicate higher

estimated risks for a given exposure level than

those based on body weights. Both methods have

their proponents.

EPA’s policies (1980 and 1986) assumed that response is proportional to daily dose per unit of

body surface area, although the latter policy allows for the use of other methods if information

is available.17 IRLG (1979) argued that there is no

one single factor to capture the differences in animal and human susceptibility and suggests that

“several species-conversion factors should be considered in estimating risk levels for humans . . . .“

The other policies did not specify what species

scaling factor to use.

Agency Practice of Quantitative

Risk Assessment

In practice, many of the choices in performing

a risk assessment for a particular chemical are specific to that chemical. These choices focus on

which particular study to use; for instance, if there

are several animal bioassays, which are of acceptable scientific quality, and of those that are acceptable, which particular study should be used? Also

at issue is which data set to use; for example, if

several tumor sites are aff ected, which one should

be used? While several policies suggest using the

most sensitive animal and tumor sites, often the

16In practice, surface area is approximated by raking the body

weight to the 2/3rd power.

“Specifically, comparative toxicologic, physiological, metabolic

and pharmacokinetic information might be useful for directly developing a cross-species extrapolation (58). However, most of the

time, these data are limited or not available.
59

policies also suggest incorporating information on

the human relevance of these tumor sites, if that

information is available.

Choices like these are inescapable in risk assessment. General guidelines will not obviate these

choices. It may not be desirable to do so either.

If the process is made routine and a “cookbook”

approach has been formulated, talented individuals with the most to contribute toward developing new approaches may be dissuaded from entering the process (86).

In discussions with OTA, agency staff often indicated that they use a flexible approach to risk

assessment, incorporating new knowledge when

it becomes available, and allowing choices to be

made case by case to develop a risk assessment

that is appropriate for a given chemical. Still, the

agencies also tend to use certain “default” assumptions in the absence of other data or considerations.” Some of these default assumptions are discussed in the written policies, although not all of

them are. To develop an understanding of the

agencies’ approaches to these issues, OTA asked

agency staff about the default assumptions used

for extrapolating from high to low doses and for

converting animal data to estimate human risk.

To extrapolate from high to low doses, EPA,

OSHA, and CPSC all use the multistage model,

and more specifically, the same computer program for the actual mathematical manipulations.

This program uses a specific mathematical algorithm to develop an equation for the doseresponse curve and then uses that equation to estimate the risk at low doses. In addition, these three

agencies often run other models (e.g., one-hit,

multihit, probit, logit, or Weibull models) to obtain a range of possible estimates (33,58,118).

Again, these three agencies differ in whether

they use the upper confidence limit or maximum

likelihood estimate. As discussed above, EPA uses

the upper confidence limit of the multistage

model, also known as the “linearized multistage

model, ” in the absence of information that would

“Computer users will recognize this use of the term “default. ”

In computer terminology, “default” usually refers to the variables,

values, or parameters that will be used unless the user specifies

otherwise.

indicate the use of another model. In published

risk assessments using the multistage model,

OSHA has used the maximum likelihood estimate

(118). CPSC also uses the maximum likelihood

estimate, although only if the data appear to be

linear at low doses (33).

FDA uses a different procedure, which usually

gives results similar to those of the linearized multistage model. This method represents a modification of the Gaylor-Kodell linear interpolation

method. In the FDA modification, the estimated

response rate at the lowest dose, where curvilinearity is no longer discernible from the data, is extrapolated linearly to the background response

rate (the tumor incidence when the exposure level

is zero) to estimate risk at low doses. With data

that are considered insufficient or of questionable quality, the upper confidence limit on the response rate is used as the starting point for this

linear extrapolation. FDA has used upper limits

on other models (e.g. multihit, logit, and Weibull

models) and found the results comparable to the

Gaylor-Kodell procedure (188).

In setting a species conversion factor for converting animal data to human risk estimates, the

four agencies split evenly on the default factor to

be used—EPA and CPSC convert on the basis of

body surface area, while FDA and OSHA convert on the basis of body weights (33,58,118,182).

For this step in risk assessment, agency staffs

are actively exploring the use of pharmacokinetic

models; with appropriate data for both humans

and animals, it is theoretically possible to perform

the cross-species conversion directly rather than

by relying on an assumption. CAG has developed

a draft risk assessment for tetrachloroethylene that

uses pharmacokinetic information (58). The other

agencies are exploring ways to use this kind of

information, both qualitatively and quantitatively, but have not yet published risk assessments

that used pharmacokinetic modeling.

Thus, the four main regulatory agencies have

chosen four different approaches to these three

issues: the method of extrapolating from high to

low doses, use of the Upper Confidence Limit or

the Maximum Likelihood Estimate, and converting data from one species to predict another specie’s response. How much these choices affect the
60

resulting risk assessments depends on the precise

nature of the data used, such as the shape of the

animal dose-response curve. In some cases, these

different approaches could lead to important

differences in estimated risk; in other cases, there

would be little difference. However, compared to

the use of models that assume a no-effects threshold, the models chosen by the four agencies will

tend to be relatively close to each other.

Agency Policies on Human

Exposure Estimation

After the dose-response characterization, the

next step is to combine the resulting mathematical representation of hazard with data on actual

human exposures. According to OSTP (1985), a

risk assessment is only as good as the human exposure estimates, although far less attention has

been paid to this aspect of the risk assessment

process. In fact, exposure is often the crucial step

in determining whether human risk is substantial

or trivial. But this is often the area where the data

are weakest. The agency policy documents generally devote only limited attention to the issues

of exposure assessment, often merely presenting

questions that should be answered.

OSTP (1979) recommended that research be

done on exposures and CPSC (1978) stated that

its staff analyses consider the nature and extent

of human exposure to products containing the regulated substance and their potential for human

uptake.

OSTP (1985) gave some attention to exposure

assessment. Exposure assessments rely largely on

monitoring data (e. g., actual measurements of

chemical concentrations in water) and modeling

(e.g., computer programs designed to predict exposure levels under a variety of assumptions). In

the appendixes to a chapter on exposure (OSTP

1985), participating agencies presented descriptions of a number of the data bases, such as on

food consumption, food additive use, modeling

techniques, and other pertinent topics.

In its summary principles, OSTP (1985) argued

that “a single generally applicable procedure for

a complete exposure assessment does not exist. ”

Exposure assessments should be tailored to provide information relevant for the risk assessment

and should describe the “strengths, limitations,

and uncertainties of the available data and models

and should indicate the assumptions made to derive the exposure estimates. ” A range or array of

exposure values is generally preferred to a single

numerical estimate.

EPA (1976) presented a list of exposure variables to identify and factors to consider in risk

assessment: known and possible exposures, data

on factors relevant to effective dose, physical and

chemical parameters, possible interaction of

agents, likely exposure levels, both time pattern

and weighted averages for total population and

subgroups with different exposures, size of groups

(and whether exposures involve children and pregnant women), adequacy of exposure estimation

methods, and uncertainty.

EPA’s Carcinogen Risk Assessment Guidelines

(EPA 1986) called for a case-by-case selection of

methods to match data and level of required sophistication and, unless there is evidence to the

contrary, for basing risk estimates on cumulative

doses received over lifetimes, expressed as average daily exposure prorated over a lifetime. Furthermore, analysts should assess the level of uncertainty in exposure assessment.

EPA has also issued separate guidelines on exposure assessment (285). The intent was that these

guidelines, “by laying out a set of questions to

be considered in carrying out an exposure assessment, should help avoid inadvertent mistakes of

omission” (285). Thus, consistency among exposure assessments would be promoted and the information developed would be in a form compatible with dose-response assessments. The text of

the guidelines, only 11 pages in the Federal Register, is largely an outline of points that analysts

should cover in exposure assessment. These include information on the properties of the chemical in question, the sources of production and distribution, exposure pathways and environmental

fate, information on measured or estimated concentrations, a description of the exposed population, and an “integrated exposure analysis. ” The

last item consists of the actual calculation of exposures, information on human dosimetry, development of exposure scenarios (occupational,
consumer, transportation, disposal, food, drinking water, ambient), and discussion of uncertainty. An issue of emerging importance for

exposure estimation involves potential human exposures to toxic chemicals from different routes.

For example, a carcinogenic chemical in drinking

water might also present a dermal and inhalation

hazard when people are taking showers.

The EPA guidelines are general and do not specify particular methods, procedures, or assumptions to use in the absence of data. The guidelines

express a preference for measured data, but recognize the need to use mathematical modeling in

many cases. In actual practice, exposure estimation has involved extensive use of computer

models in the absence of exposure measuremerits. ’9 The EPA guidelines encourage “the development of realistic assessments based on the

best data available,” rather than the use of “worstcase assessments. ” But EPA “will err on the side

of public health when evaluating uncertainties,

when data are limited or nonexistent” (285). EPA’s

Office of Toxic Substances has developed nine

volumes presenting methods for assessing exposure in the ambient environment, chemical disposal, drinking water, occupational exposure,

consumer exposure, food contamination, transportation-related spills, and on methods for

enumerating and characterizing exposed populations (342).

Two of the guidelines present specific assumptions used in risk assessment calculations. EPA

(1980), for the water quality criteria documents,

provided an assumed average drinking water consumption of 2 liters of water per day and average fish consumption of 6.5 grams of fish per day.

FDA (1985), for the SOM guidelines, states that

allowable drug residue level will be set after correcting for food intake in total human diet. For

these calculations, FDA specifies various “food

factors” which imply that up to one-third of diet

might be cattle, pig, sheep, or poultry muscle or

poultry eggs, and 100 percent of diet might be

cow’s milk.

‘“EPA, for example, has been criticized by its Science Advisory

Board and others for an overreliance on computer modeling for exposure assessment (156),

61

Risk Characterization

The first issue in risk characterization is whether

to make the characterization quantitative. The

Federal agencies are all using quantitative risk

assessment today, although some observers urge

caution in the use of these quantitative approaches

(8,156).

Different approaches to whether quantitative

estimates are possible or desirable are found in

the policies. CPSC (1978) and OSHA (1980) argued

that quantitative risk assessment would be used

at those agencies only for setting priorities. Court

decisions and the general regulatory environment

have superseded that stand, and both agencies

today prepare quantitative risk assessments.

OSTP (1979) admitted that “extrapolation from

the animal model to humans represents something

of a leap of faith, ” but nevertheless recommends

that quantitative potency estimates should be used

in determining the human risk posed by a carcinogen and that assessment of relative potencies “will

aid agencies in the establishment of regulatory priorities and in the selection of appropriate regulatory action. ” EPA (1976, as well as subsequent

EPA policies) accept quantitative estimation as important for setting regulatory standards, but indicate it “should be regarded only as rough indications of effect. ”

EPA (1986) presents several options for quantitative characterization of risk:

● unit risk—’’excess lifetime risk due to continuous constant lifetime exposure of one unit

of carcinogen concentration, ”

. dose corresponding to a given level of risk,

● individual risks—excess individual lifetime

risk, and

● population risk—excess number of cancers

in an exposed population.

Individual and population risks are those most

used in policy debates. Both of these estimates incorporate information on potency from the doseresponse characterization with estimates of exposures. Individual risk is the increase in the probability of disease or death for an individual in a

lifetime. It is often expressed as the number of

deaths per thousand or million similarly exposed
62

persons. Thus, exposure to a particular carcinogen might present a 1 in 1,000 lifetime risk. Population risk involves the number of excess cases

of disease found in the exposed population. Thus

among 70,000 people exposed to a 1 in 1,000 lifetime risk, there would be 70 excess cancer deaths

associated with this exposure. Some exposures

might present high individual risks among a relatively small subgroup in the population, yet also

present a low population risk (because of the small

number of people exposed). What to do in these

situations is an important regulatory issue. Most

of the policies are silent on this issue, although

OSTP (1985) suggests that agencies consider identifying high-risk populations.

EPA (1986) also cautioned against using more

than one significant figure in the quantitative estimates, although their published potency estimates

in the past frequently had three significant figures.

(See table 3-24 in ch. 3.)

EPA (1980) used a boilerplate for its risk summary of the water quality criteria documents:

[name of chemical] is a carcinogen, exposures to

carcinogens should be zero, but may not be attainable. “Therefore, the levels which may result

in incremental increase of cancer risk over the lifetime are estimated at 10-5

, 10-6, 10-7. ” The corresponding estimates for the particular chemical

were then presented.

Treatment of Uncertainty

It is also important to describe uncertainties in

the characterization of the risk. There is little opposition to discussing uncertainties and assumptions in risk assessments. The agency policies differ, however, on the utility of developing a range

of estimates using different extrapolation models. 20 For example, EPA (1976) urges that “where

appropriate, a range of estimates should be given

on the basis of several modes of extrapolation. ”

OSTP (1985) states that it is important to discuss

the various sources of uncertainty, including statistical uncertainty, variability introduced by the

chosen extrapolation model, and variability asso20Although there are other sources of uncertainty in risk assessments, much of the discussion in policies on this point concerns the

choice of extrapolation model.

ciated with interspecies scaling. The uncertainty

in the choice of model can be characterized by

indicating the range of estimated risks that can

be developed using different plausible models.

EPA (1980) and FDA (1985) on the other hand

argued that little is gained by adding estimates

from several different models. EPA (1980) went

so far as to state that this would “add no additional scientific information while at the same time

would create confusion and thereby undermine

the utility of risk estimates.” OSTP (1985) advises

agencies to distinguish clearly among facts, consensus, assumptions, and science policy decisions.

Although it is not clear that this effort will actually reduce regulatory controversies, it may clarify

the issues in dispute and outline the areas of greatest uncertainty.

New Areas for Risk

Assessment Policy

Two topics have been given increased attention

in recent years: possible distinctions among carcinogens based on their mechanisms of action and

consideration of the pharmacokinetics of toxic

chemicals within the body. The former received

considerable attention and argument early in the

Reagan Administration when suggestions were

made that regulatory distinctions could be made

based on carcinogenic mechanisms.

Distinctions Based on Mechanism

The development of cancer consists of stages.

These are typically called initiation, promotion,

and progression. Initiation involves an alteration

in a cell’s genetic material, an alteration that can

remain latent (without apparent disease) for years.

Promotion involves the expression of genetic information and the transformation of latent initiated cells into tumors. Progression consists of the

growth of tumors and the development of metastasis in distant tissues.

Some chemicals are primarily initiators; others

act only as promoters. Many chemicals are both

initiators and promoters and are termed complete

carcinogens.

Because they can directly damage genetic material, leading to creation of initiated cells, and
63

because such damage might be from an interaction with a very small amount of the chemical and

may not be reversible, it is generally felt that initiators would not exhibit a no-effects threshold.

It is possible that the mechanism of promotion

involves alteration in body chemistry, cellular

growth and repair, and other processes. Because

these alterations may be reversible and may not

be harmful at relatively low doses, it has been suggested that there may be safe thresholds for these

agents (358,359).

Weisburger and Williams have suggested the

terms genotoxic and epigenetic to distinguish carcinogens based on their mechanisms (358,359).

Other distinctions made, though with different

meanings, are genotoxic and nongenotoxic, and

direct and indirect carcinogens. But while such distinctions have been hypothesized, most scientists

do not believe that chemicals in these groups can

be reliably distinguished (98,157,258,351,356).

This is particularly the case because many carcinogenic chemicals affect both initiation and promotion. While research on mechanisms is moving rapidly, there is currently no accepted group

of tests for determining the mechanism of action

for carcinogenic chemicals.

Moreover, promoters may themselves be very

potent. “Dioxin” (2,3,7,8-TCDD), the most potent animal carcinogen known, may be acting as

a promoter. Finally, some argue that the doseresponse curve for indirect carcinogens will be linear at low doses, just as it is for direct carcinogens (86). An important argument on this point

is that if it is assumed that exposure to a carcinogen adds to the background risk of cancer, the

dose-response curve will be linear in the low-dose

region (37).

While the issue has received enhanced attention

in recent years, it is one that has been addressed

in some of the earlier policies as well. In general,

agency policies have refused to give a blanket endorsement of regulatory distinctions based on

mechanism, although several appear willing to entertain an argument, with supporting documentation, that a substance acts only through an indirect mechanism.

EPA (1980) saw no currently satisfactory way

of estimating risk for “epigenetic” agents and until mechanisms are better understood, will continue to use the linear no-threshold model. EPA

(1986) generally considers substances positive in

bioassays to be complete carcinogens, “unless

there is evidence to the contrary. ” Individual consideration will be given to cases where the substance is positive in special tests for initiation, promotion, or cocarcinogenicity, but negative in

long-term bioassays. NCAB (1977) wanted additional tests before extrapolating to humans when

a substance tests positive in a bioassay in which

the animals were also treated with a known carcinogen or cocarcinogen. OSHA (1980) allowed

consideration of the argument that an indirect

mechanism is involved and that this would not

occur under conditions of human exposure. IRLG

(1979) required “rigorous documentation” that a

positive animal bioassay does not represent a

complete carcinogenic process, but is due solely

to an enhancing factor. IRLG (1979) also noted

that in considering indirect mechanisms, promoters, and metabolic pathways, it would consider

evidence, but expressed concern that false-negative judgments be avoided.

Incorporation of Pharmacokinetics

Exposure to a drug or chemical can lead to a

variety of chemical and biological reactions in the

body. The substance can be absorbed into the

body, metabolized into other substances, distributed to other organs and tissues, or removed from

the body. The general term for all of these processes is pharmacokinetics (171).

The various biochemical pathways in the body

that activate, metabolize, detoxify, transport, and

excrete chemicals will determine the relationship

between the administered doses and the effective

dose. As shown in figure 2-3, this relationship

might be linear, but may not be. Either activation or detoxification mechanisms could become

saturated or overwhelmed. In these cases, the

administered dose (the dose externally administered to the animal) will not be proportionate to

the effective dose (the amount of the chemical or

its metabolizes) that actually reach the target tissue, and qualitatively different effects may occur.

The shape of the curve relating administered dose
0 4

Figure 2-3.—Possible Types of Relationships Between

Administered and Effective Dose

D*

D

Possible relations between administered dose, D, and effective dose

at the target (e.g. DNA), D’, for several kinetic models: a) simple firstorder kinetics; b) saturation of the activation system; c) saturation of

detoxification or repair systems; and d) combination of b) and c).

SOURCE: D.B. Heal, N.L. Kaplan, and M.W. Anderson, “implication of Nonlinear

Kinetics on Risk Assessment in Carcinogenesis,” Science 219:1032-37,

1983.

with effective dose depends on the particular pathways used and the levels at which each becomes

saturated .2*

While some observers hope that analysis of

pharmacokinetics will refine risk assessments and

improve regulatory decisions, there is much that

is not understood, and there are practical difficulties in undertaking the experiments and analyzing the data. Until recently, the agencies have not

attempted to include quantitative modeling of a

chemical’s pharmacokinetics in their quantitative

risk assessments, However, even some of the

earlier policies place a value on information concerning the metabolism of carcinogenic compounds.

EPA (1976) stated that a risk analysis should

describe a substance’s metabolic characteristics

21Note that each of the four curves in figure 2-3 assumes the absence of a no-effects threshold.

and similarities to other known classes of carcinogens at high and low doses and in different species. EPA (1980) stated that pharmacokinetic

information can be useful for interspecies comparisons and estimating human risk. Further, EPA

stated that relevant metabolic differences among

species should be considered. EPA (1986) mandated a summary of relevant metabolic and pharmacokinetic data and suggested that this information might affect choice of a high to low dose

extrapolation model. With this information or

other evidence on the cancer mechanism, an extrapolation using a model other than the linearized multistage model “might be considered more

appropriate on biological grounds. ”

FIFRA (1984) also desired a summary of available pharmacokinetic data. In an example, the

policy suggested that an evaluator should then

consider the available metabolic and pharmacodynamic data for an explanation of the shape of

the dose-response curve. Although not stated in

the text, the data in this example appear to be

from a study of rats exposed to formaldehyde.

FIFRA (1984) suggested that a “threshold dose has

been exceeded” in describing a very curvilinear

dose-response curve.

OSHA (1980) set forth detailed requirements

for arguments that metabolic differences between

animals and humans justify the conclusion that

a positive animal carcinogen does not pose a human health risk. This policy stated that OSHA

would also consider a substance to be a carcinogen if it is metabolized into one or more potential occupational carcinogens. IRLG (1979) stated

that while knowing the dose at the target organ

is the ideal and that study of a substance’s pharmacokinetics can in theory provide that information, there are still many uncertainties about

metabolic pathways in humans and considerable

variation within the human population. OSTP

(1985) urged that the extrapolation model chosen

needs to be consistent with available information

on pharmacokinetics and target tissue dose.

Use of pharmacokinetic modeling is frequently

hampered by lack of data and by our incomplete

knowledge about which metabolizes are the ultimate carcinogens. Obtaining these data in humans
65

for known animal carcinogens would require deliberately exposing people to suspect carcinogens

—an enterprise that is ethically objectionable.

Classification of Carcinogens

Some policies provide for classifying substances

by the nature or strength of the evidence for carcinogenicity. Regulatory agencies that provide

such classifications on major statements include

OSHA (1980), CPSC (1978), and EPA (1986, and

the proposed EPA airborne carcinogen policy in

1979). NTP also has a classification of “levels of

evidence” for the results of the long-term carcinogenicity studies. Finally, there is the carcinogen classification scheme of IARC.

Boxes 2-B through 2-G summarize the various

classification systems. Except for the NTP “levels

of evidence, ” which is designed solely for evaluating animal test results, all of the systems accept

human evidence and accord the highest overall

classification to substances shown by human epidemiologic studies to be carcinogenic. For example, for IARC this is Group 1, for EPA (1986),

Group A.

All of the policies accept the use of animal data

alone for suggesting a carcinogenic hazard to humans, although there are some differences in the

nature of the required evidence. A significant increase in malignant tumors in two or more species or two or more independently conducted

studies in the same species is considered “sufficient” evidence by IARC and EPA (1986), “strong”

evidence by CPSC (1978), and enough to bring

the substance into “Category I“ of OSHA (1980).

Positive results in only one animal species are considered to be “limited” evidence by IARC and EPA

(1986), but would be adequate to place the substance in the “high probability” category of the

EPA airborne carcinogen policy (1979). Both

CPSC (1978) and OSHA (1980) indicated that

positive results in one species with supporting or

concordant short-term test results would also lead

to classification as a carcinogen (CPSC: strong

evidence; OSHA: Category I). In addition, both

agencies indicate that in certain circumstances

they could decide to classify a substance as a carcinogen even without such supporting data. Thus,

for both CPSC and OSHA, as well as EPA (1979),

a substance could be classed as a carcinogen of

regulatory interest based on a positive bioassay

in single species.

All the schemes will classify substances as carcinogens based on both benign and malignant

tumors. Both IARC and EPA (1986) include the

possibility of downgrading a substance to the

“limited evidence” category if the response is an

increase in tumors that have a high spontaneous

background rate. The classic example of this is

an increased incidence of mouse liver tumors.

The IARC classification scheme presented in

box 2-B represents the results of a recent modification. The major changes involved creation of

a new Group 4 for agents probably not carcinogenic to humans and the criteria for Group 2.

Group 2A (probably carcinogenic) will generally

be used for agents with limited evidence in humans and sufficient evidence in animals. Group

2B (possibly carcinogenic) will be used for agents

that have only limited evidence in humans without sufficient evidence in animals, inadequate or

no data in humans but sufficient evidence in animals, and inadequate or no data in humans and

limited evidence in animals when there is other

supporting data. Generally agents will be classified in Group 4 based on combined evidence from

animals and humans which indicate a lack of carcinogenicity (99).

The EPA weight-of-the-evidence classification

system was developed as an adaptation of an

earlier version of the IARC classification system.

EPA (1986) quotes extensively the IARC definitions of “sufficient” and “limited” evidence. The

EPA classification has regulatory meaning as well.

The regulation of chemicals in drinking water depends on the weight-of-the-evidence classification.

In addition, the weight-of-the-evidence classifications were used in developing adjustments of the

reportable quantities of chemicals covered under

CERCLA. (See ch. 3.)
66

Box 2-B. —1987 Classification of Carcinogens by the International Agency for Research on Cancer (99)

Degree of Evidence for Carcinogenicity to Humans and to Experimental Animals

and Supporting Evidence

It should be noted that these categories refer only to the strength of the evidence that these agents

are carcinogenic and not to the extent of their carcinogenic activity (potency) nor to the mechanism involved. The classification of some agents may change as new information becomes available.

Human Carcinogenicity Data.—The evidence relevant to carcinogenicity from studies in humans is

classified into one of the following categories:

Sufficient Evidence of Carcinogenicity. —The Working Group considers that a causal relationship has

been established between exposure to the agent and human cancer. That is, a positive relationship has been

observed between exposure to the agent and cancer in studies in which chance, bias, and confounding could

be ruled out with reasonable confidence.

Limited Evidence of Carcinogenicity. —A positive association has been observed between exposure to

the agent and cancer for which a causal interpretation is considered by the Working Group to be credible,

but chance, bias, or confounding could not be ruled out with reasonable confidence.

Inadequate Evidence of Carcinogenicity. —The available studies are of insufficient quality, consistency,

or statistical power to permit a conclusion regarding the presence or absence of a causal association.

Evidence Suggesting Lack of Carcinogenicity.—There are several adequate studies covering the full

range of doses to which human beings are known to be exposed, which are mutually consistent in not showing

a positive association between exposure to the agent and any studied cancer at any observed level of exposure. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the cancer sites,

circumstances and doses of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studies can never be excluded.

In some instances, the above categories may be used to classify the degree of evidence for the carcinogenicity of the agent for specific organs or tissues,

Experimental Carcinogenicity Data.—The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

Sufficient Evidence of Carcinogenicity. —The Working Group considers that a causal relationship has

been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms . . . in (a) two or more species of animals or (b) in

two or more independent studies in one species carried out at different times or in different laboratories

or under different protocols.

Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type

of tumor, or age at onset.

In the absence of adequate data on humans, it is biologically plausible and prudent to regard agents

for which there is sufficient evidence of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans.

Limited Evidence of Carcinogenicity. —The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g., (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct, or interpretation of the study; or (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain
67

neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidence in certain

strains.

Inadequate Evidence of Carcinogenicity. —The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations.

Evidence Suggesting Lack of Carcinogenicity. — Adequate studies involving at least two species are

available which show that, within the limits of the tests used, the agent is not carcinogenic. A conclusion

of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumor sites, and doses

of exposure studied.

Supporting Evidence of Carcinogenicity .—The other relevant data judged to be of sufficient importance as to affect the making of the overall evaluation are indicated.

Overall Evaluation

Finally, the total body of evidence is taken into account; the agent is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent

is a matter of scientific judgment, reflecting the strength of the evidence derived from studies in humans

and in experimental animals and from other relevant data.

Group 1: The Agent Is Carcinogenic to Humans.—This category is used only when there is sufficient

evidence of carcinogenicity in humans.

Group 2.—This category includes agents for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as agents for which, at the other extreme, there are

no human data but for which there is experimental evidence of carcinogenicity. Agents are assigned to

either 2A (probably carcinogenic) or 2B (possibly carcinogenic) on the basis of epidemiological, experimental, and other relevant data.

Group 2A; The Agent Is Probably Carcinogenic to Humans.-This category is used when there is limited

evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals.

Exceptionally, an agent may be classified into this category solely on the basis of limited evidence of carcinogenicity in humans or of sufficient evidence of carcinogenicity in experimental animals strengthened

by supporting evidence from other relevant data.

Group 2B: The Agent Is Possibly Carcinogenic to Humans.—This category is generally used for agents

for which there is limited evidence in humans in the absence of sufficient evidence in experimental animals.

It may also be used when there is inadequate evidence of carcinogenicity in humans or when human data

are nonexistent but there is sufficient evidence of carcinogenicity in experimental animals. In some instances,

an agent for which there is inadequate evidence or no data in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in

this group.

Group 3: The Agent Is Not Classifiable as to Its Carcinogenicity to Humans.—Agents are placed in

this category when they do not fall into any other group.

Group 4: The Agent Is Probably Not Carcinogenic to Humans.—This category is used for agents for

which there is evidence suggesting lack of carcinogenicity in humans together with evidence suggesting lack

of carcinogenicity in experimental animals. In some circumstances, agents for which there is inadequate

evidence of or no data on carcinogenicity in humans but evidence suggesting lack of carcinogenicity in

experimental animals, consistently and strongly supported by a broad range of other relevant data, may

be classified in this group.
68

●

●

●

●

●

Box 2-C.–1986 Classification of Carcinogens by National Toxicology Program (255)

Clear Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a

dose-related: (i) increase of malignant neoplasms, (ii) increase of a combination of malignant and benign

neoplasms, or (iii) marked increase of benign neoplasms if there is an indication from this or other studies

of the ability of such tumors to progress to malignancy.

Some Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a

chemically related increased incidence of neoplasms (malignant, benign, or combined) in which the strength

of the response is less than that required for clear evidence.

Equivocal Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing

a marginal increase of neoplasms that may be chemically related.

No Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing no chemically related increases in malignant or benign neoplasms,

Inadequate Study of Carcinogenic Activity is demonstrated by studies that because of major qualitative

or quantitative limitations cannot be interpreted as valid for showing either the presence or absence of

carcinogenic activity.

When a conclusion statement for a particular experiment is selected, consideration must be given to key

factors that would extend the actual boundary of an individual category of evidence. This should allow

for incorporation of scientific experience and current understanding of long-term carcinogenesis studies in

laboratory animals, especially for those evaluations that may be on the borderline between two adjacent

levels.

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

These

These considerations should include:

the adequacy of the experimental design and conduct;

occurrence of common versus uncommon neoplasia;

progression (or lack thereof) from benign to malignant neoplasia as well as from preneoplastic lesions;

some benign neoplasms have the capacity to regress but others (of the same morphologic type)

progress. At present, it is impossible to identify the difference. Therefore, where progression is known

to be a possibility, the most prudent course is to assume that benign neoplasms of those types have

the potential to become malignant;

combining benign and malignant tumor incidence known or thought to represent stages of progression in the same organ or tissue;

latency in tumor induction;

multiplicity in site-specific neoplasia;

metastasis;

supporting information from proliferative lesions (hyperplasia) in the same site of neoplasia or in

other experiments (same lesion in another sex or species);

the presence or absence of dose relationships;

the statistical significance of the observed tumor increase;

the concurrent control tumor incidence as well as the historical control rate and variability for a

specific neoplasm;

survival-adjusted analyses and false positive or false negative concerns;

structure-activity correlations; and

in some cases, genetic toxicology.

considerations together with the definitions as written should be used as composite guidelines for

selecting one of the five categories. Additionally, the following concepts (as patterned from the International Agency for Research on Cancer Monographs) have been adopted by the NTP to give further clarification of these issues:
69

The term chemical carcinogenesis generally means the induction by chemicals of neoplasms not usually

observed, the induction by chemicals of more neoplasms than are generally found, or the earlier induction

by chemicals of neoplasms that are commonly observed. Different mechanisms may be involved in these

situations. Etymologically, the term carcinogenesis means induction of cancer, that is, of malignant neoplasms;

however, the commonly accepted meaning is the induction of various types of neoplasms or of a combination of malignant and benign neoplasms. In the Technical Reports, the words tumor and neoplasm are used

interchangeably.

Box 2-D.–1986 Classification of Carcinogens by the Environmental Protection Agency (284)

Group A—Human Carcinogen:

This group is used only when there is sufficient evidence from epidemiologic studies to support a causal

association between exposure to the agents and cancer.

Group B—Probable Human Carcinogen:

This group includes agents for which the weight of evidence of human carcinogenicity based on epidemiologic studies is “limited” and also includes agents for which the weight of evidence of carcinogenicity

based on animal studies is “sufficient. ” The group is divided into two subgroups. Usually, Group Bl is

reserved for agents for which there is limited evidence of carcinogenicity from epidemiologic studies. It

is reasonable, for practical purposes, to regard an agent for which there is “sufficient” evidence of carcinogenicity in animals as if it presented a carcinogenic risk to humans. Therefore, agents for which there

is “sufficient” evidence from animal studies and for which there is “inadequate evidence” or “no data” from

epidemiologic studies would usually be categorized under Group B2.

Group C—Possible Human Carcinogen:

This group is used for agents with limited evidence of carcinogenicity in animals in the absence of

human data. It includes a wide variety of evidence, e.g., (a) a malignant tumor response in a single wellconducted experiment that does not meet conditions for sufficient evidence, (b) tumor responses of marginal statistical significance in studies having inadequate design or reporting, (c) benign but not malignant

tumors with an agent showing no response in a variety of short-term tests for mutagenicity, and (d) responses of marginal statistical significance in a tissue known to have a high or variable background rate.

Group D—Not Classifiable as to Human Carcinogenicity:

This group is generally used for agents with inadequate human and animal evidence of carcinogenicity

or for which no data are available.

Group E—Evidence of Non-Carcinogenicity for Humans:

This group is used for agents that show no evidence for carcinogenicity in at least two adequate animal tests in different species or in both adequate epidemiologic and animal studies.

The designation of an agent as being in Group E is based on the available evidence and should not

be interpreted as a definitive conclusion that the agent will not be a carcinogen under any circumstances.
70 —

BOX 2-E.— 1979 Classification of Carcinogens

in the EPA Airborne Carcinogen Policy (324)

Identify carcinogens based on EPA guidelines,

supplemented by IRLG guidelines, judgments

based on quality and weight of evidence, classify into high, moderate, or low, based on probability of human carcinogenicity

● high probability —’’best” or “substantial”

evidence exists from epidemiologic and/or

at least one mammalian study;

● moderate probability —’’suggestive” evidence exists from epidemiologic, animal, or

“short-term” studies; and

● low probability—only “ancillary” evidence

exists, such as from structural correlations,

or for which epidemiologic or animal results

are judged to indicate low probability.

Box 2-F.—1982 Classification of Carcinogens

by the Occupational Safety and

Health Administration (276)

Category I Potential Carcinogens. -If substance meets definition of potential occupational

carcinogen in: 1) humans, 2) a single mammalian

species in a long-term bioassay where the results

are in concordance with some other scientifically

evaluated evidence of a potential carcinogenic

hazard, 3) in a single mammalian species in an

adequately conducted long-term bioassay, in

appropriate circumstances where [OSHA] determines the requirement for concordance is not

necessary. Evidence of concordance is any of the

following: positive results from independent testing in the same or other species, positive results

in short-term tests, or induction of tumors at injection or implantation sites.

Category II Potential Carcinogens.–1) Meets

criteria for category I, but the evidence is only

“suggestive” or 2) meets criteria for category I

in a single mammalian species without evidence

of concordance.

The requirement for concordance may be

waived in “cases where the evidence has been

carefully scrutinized and found to be unusually

compelling, ” including the induction of many unusual tumors or early deaths for most of the exposed animals.

Box 2-G.—1978 Classification of Carcinogens by

the CPSC (228)

Category A—Strong Evidence:

1. NCI has issued a finding that the substance

is an animal or human carcinogen,

2. substance significantly increases incidence

or reduces time to onset of benign or malignant neoplasms in humans in exposed compared to nonexposed, or

3. substance significantly increases incidence

or reduces time to onset of one or more

types of benign or malignant neoplasms in

treated compared to control groups [of experimental animals].

Ordinarily, positive animal results must derive

from systemic distribution of substance and must

be obtained in:

● two animal species; or

● one species when replicated in a second experiment using independent control groups;

or

● one species of test animal when supported

by a battery of well designed and soundly

conducted relevant short-term tests; or

Ž CPSC finds that there is other evidence

sufficiently compelling to classify substance

in Category A. Thus classification may be

based on single, unreplicated long-term animal study.

Category B—Evidence is Suggestive:

1. human or animal data are suggestive but

not conclusive because they are statistically

inconclusive or methodologically deficient

but nonetheless tend to support carcinogenicity;

2. positive results in one or more short-term

tests, but not confirmed in human or animal studies;

3. positive results in only one unreplicated

long-term animal study which is not compelling enough to classify in Category A;

absence of positive short-term results.

Category C:

Substances which are members of chemical

classes which include known carcinogens and

other substances about which questions have

been raised, but with very limited evidence.

Category D:

Reclassified substances.
71

AGENCY POLICIES ON CARCINOGEN RISK MANAGEMENT

Regulatory Procedures

Compared to the problems of identifying and

assessing carcinogenic risk, relatively little attention is given in the various agency policies to the

topic of how to reduce, eliminate, or control the

risks posed by carcinogens. Only CPSC (1978),

EPA (1979), OSHA (1980), and FDA (1985) give

any details beyond a summary of the agency’s

statutory mandate on the kind of regulatory action that can be anticipated after identifying a carcinogen. In addition, OSTP (1979) suggests focusing regulatory action on particular exposures to

improve the ratio of benefits to costs.

Most of these statements are in documents that

have the official status of proposals (EPA 1979

and FDA 1985), or that have been suspended

(OSHA) or withdrawn (CPSC 1978). However,

in communication with OTA, EPA staff suggest

that the airborne carcinogen policy (1979) reflects

the broad outlines of their approach, FDA staff

stated in their proposed SOM (1985) that they

would follow the procedures outlined in it until

it was published in final form. OSHA has not

taken action to revoke their cancer policy.

The basic policy outlined by three of the documents is a very protective approach for eliminating or substantially reducing carcinogen exposures. CPSC (1978) states a general policy of

not permitting “known carcinogens to be intentionally added to consumer products if they can

be absorbed, inhaled or ingested . . . .“ CPSC

(1978) required the use of substitutes for identified carcinogens or reduction to the lowest attainable level” until substitutes can be found. However,

actual practice at CPSC since 1978 demonstrates

that CPSC has followed a less conservative course

in addressing chemical hazards. As discussed in

chapter 3, CPSC has often deferred to voluntary

industry action and CPSC-mandated labeling of

hazardous consumer products to reduce exposures

(81).

For Category I carcinogens (for which the evidence is clear), OSHA (1980) originally required

that exposures be reduced to the lowest feasible

level, using engineering controls and work practices (and not through use of respirators). If suitable, safer substitutes are found, OSHA will set

permissible exposures at zero to encourage substitution. The EPA airborne carcinogen policy

(288) mandates that for identified carcinogens, the

standards issued under section 112 of the Clean

Air Act will, at a minimum, require use of best

available technology. If the risk remaining after

application of the best available technology is still

unreasonable, EPA will consider mandating further control.

In all three cases, the agencies state that they

do not believe that safe thresholds exist for carcinogens. This view, combined with their interpretations of statutory mandates, leads them to

require that exposures be reduced as much as possible through the use of technology and substitution.

In its SOM paper, FDA argues that it follows

a protective approach in setting a maximum lifetime risk cutoff of 1 in 1 million and in using upper bound risk estimates for determining the added risk of one permitted animal drug residue. In

the U.S. population of 240 million, assuming that

everyone is exposed, this would imply a maximum of 240 deaths. FDA suggests that because

of the assumptions behind the development of

their risk estimates, the actual risks are lower than

that. In fact, they argue that it is likely that no

one will actually die as a result of these exposures.

The FDA policy is in fact the only one to adopt

a risk level that it deems to be “safe. ” Other agencies may do this informally and implicitly; FDA

alone has done this explicitly.

OSHA’s 1980 policy is the most detailed in

describing regulatory procedures that will be followed if OSHA identifies a substance as an occupational carcinogen. In addition to regulating

Category I carcinogens to the lowest feasible level

(see above), OSHA will regulate what it calls Category II carcinogens (for which the evidence is

only suggestive) in a manner consistent with statutory requirements. OSHA does not seem willing to force substitution, set a permissible exposure limit, or require compliance plans, hygiene

facilities, and regulated areas in the case of substances with only suggestive evidence of carcinogenicity. For Category II substances, OSHA is
72

also to ask for additional research from the appropriate agency.

The OSHA policy further provided for the publication of lists–annual candidate lists of substances under scientific review and semiannual priority lists of the substances with the agency’s

highest priority ranking. Only one of these lists

was ever published (277). In 1981, OSHA suspended the publication of these lists.

Finally, in an attempt to increase the timeliness

of agency action, the OSHA policy set a number

of specific deadlines for agency action. For example, a final standard was to be published within

120 days from the end of a hearing or 90 days

from the end of a posthearing comment period,

whichever is earlier. This time may be extended

for one more 120-day period, unless important

new evidence is found:

Regulatory and Research

Some of the policies also give

Priorities

guidance on setting regulatory and research priorities. In particular, the EPA airborne carcinogen policy and the

OSHA cancer policy provide some general statements about setting priorities. These are very general and probably provide only limited insight into

decisionmaking at either agency. The magnitude

of the exposed population and the availability of

controls or the low cost of applicable controls

appears in both policies. The EPA airborne carcinogen policy explicitly refers to estimated carcinogenic potency and the upper bound incidence

associated with exposures, both presumably derived from EPA’s quantitative risk assessments.

The policy refers to risk estimates for the most

highly exposed individuals and the

risk.

OSHA (1980) rejected quantitative

ment for setting the exposure level in

population

risk assessan occupational health standard; instead the policy was to

regulate down to the lowest level feasible. However, it did suggest that quantitative risk assessment could be used in setting priorities. As discussed in other sections of this background paper,

this policy was changed in response to court decisions. OSHA (1980) also mentioned that they

would consider a substance’s molecular structure,

the potential for controls to prevent other adverse

occupational and environmental effects, pending

actions by other agencies, and OSHA’s other responsibilities before taking action on a chemical.

OFFICE OF MANAGEMENT AND BUDGET POLICY ON

CARCINOGEN RISK ASSESSMENTS

Since 1981, the Office of Management and Budget (OMB) has had an important, if not central,

role in many decisions on regulatory policy

through its review of agency proposals and final

rules. Each of those actions takes place case by

case as OMB interprets the requirement for costbenefit analysis contained in Executive order

12291 and judges the desirability of particular regulations. Summarizing such case-by-case interpretation is difficult, in part because much of it takes

place in private meetings between OMB officials,

agency officials, and others. In this section, OTA

will not attempt such a summary.

OMB has publicly indicated its concern over

several areas of carcinogen risk assessments, and

its expressed opinions on these matters are contrary to the general consensus that has evolved

in the agency policies. OMB’s general position is

that the use of many “conservative” assumptions

(in these cases, assumptions designed to err on the

side of caution and minimize the chances of understating the true risk), will compound each other,

guaranteeing that the estimated risk is overstated.

If the estimated risks are overstated, regulatory

decisions will not be as efficient or as cost-effective

as they could be.22

For hazard identification and dose-response

assessment, OMB concern involves assumptions

about the treatment of benign tumors, selection

of the most sensitive species and sex for risk assess-

‘

z

For an academic discussion of this issue, see ref. 149.
73

ments, and the use of conservative high- to lowdose extrapolation techniques. On benign and

malignant tumors, OMB suggests that because not

all benign tumors become malignant, use of the

benign tumor data in the risk assessment “can

overstate the real risk present. ” Regarding choice

of data for the risk assessment, OMB argues that

use of the most sensitive species and sex will bias

the risk assessment and that a “more accurate”

estimate would be derived from a “weighted average of all the scientifically valid, available information. ” On the choice of extrapolation technique, OMB is worried about use of the upper

confidence limit, suggesting that “such an extrapolation has a 95 percent chance of overstating the

true risk. ” In fact, OMB is misinterpreting the

meaning of the upper bound estimates prepared

by the regulatory agencies.

In regard to exposure assessment, OMB expresses opinions on the use of worst-case environmental scenarios, the assumption of lifetime

exposure, and the focus of regulation being placed

on the most highly exposed individuals. The

worst-case scenarios are used to simplify the tasks

of estimating risks and setting standards. OMB

is worried that these worst-cage conditions are not

representative of actual conditions throughout the

Nation. It is usually assumed that people might

be exposed to a lifetime of drinking contaminated

water or might spend their entire lives working

with the same hazards. OMB thinks that this assumption can bias upward the estimates of risk

because people move and change jobs. Finally,

OMB expresses concern about basing regulations

on the maximally exposed individual who has the

worst combination of exposures (350).

One example of the implementation of OMB’s

approach may be found in OMB’s comments to

OSHA about OSHA’s proposed regulation of occupational formaldehyde exposures. In those comments, OMB surveyed the epidemiologic literature on formaldehyde exposures and cancer and

concluded that formaldehyde is not a human carcinogen because there is little consistency in the

tumor sites among 19 different studies and little

evidence that the observed excesses are actually

related to the level of exposures. They cited, in

addition, a recent epidemiologic study conducted

by NCI, which was also negative. The approach

embodied in most agency policies is to use negative epidemiologic studies only to estimate an upper bound on estimated risk and not to use these

studies to dispute positive animal evidence. In

fact, the position of the agency policies is that

positive animal evidence outweighs negative human evidence. In contrast to this, OMB used the

human evidence to cast doubt on the validity of

the animal evidence. OMB also argued that the

pharmacokinetics of formaldehyde exposure predict that carcinogenic effects will occur only at

high doses that overwhelm the body’s protective

mechanisms at the exposure sites.

For developing its own quantitative dose-response

assessment, OMB follows an approach to selecting animal data and extrapolating from high to

low doses that is different from that used by the

regulatory agencies. Instead of selecting the most

sensitive sex, species, and strain or choosing one

with the biologically most plausible response,

OMB combined the animal responses from six different studies in three different species. In the case

of formaldehyde this has a large effect on estimated risk because the studies are clearly positive only in rats; for mice and hamsters, the

studies are largely negative. Thus, the OMB approach uses both positive and negative data and

calls it a weight-of-evidence approach.

OMB then recalculated the extrapolation from

high to low doses using several mathematical

models—the multistage model and several models

that do not incorporate low-dose linearity assumptions—and also incorporating different exposure

scenarios and estimates of effective or delivered

dose. On the basis of these calculations OMB concluded that the “carcinogenic risk of formaldehyde

to workers is likely to be de minimis, ” that is, less

than 1 in a billion (349).

OSHA has not issued its final formaldehyde

rule. In this particular instance, it is not clear how

persuasive OMB’s arguments will be to OSHA.

Nor is it clear how strongly OMB will push its

position about risk assessment assumptions and

de minimis risks on the agencies in particular cases

or if it will expect the agencies to rewrite their general guidelines.
74

CONCLUSIONS

Federal agency guidelines are generally consistent on major features of animal bioassay design,

specifying testing in two animal species and generally requiring use of three dose groups and a

control group. The guidelines agree that a study

must set the highest dose as high as possible without shortening the animals’ lives because of noncarcinogenic toxic effects.

Agency policies value epidemiologic studies as

the most conclusive evidence for human carcinogenicity, generally presume that substances carcinogenic to animals in long-term bioassays

should be treated as presenting a hazard to humans, and treat short-term test results as supportive information. Analyses of structure-activity

relationships are used mostly when no other data

are available.

The policies state that the agencies will use

animal data derived from use of the maximum

tolerated dose and will treat the appearance of

malignant or benign tumors as evidence for carcinogenicity, except when the benign tumors are

of a type that does not progress to malignancy.

Policies usually state that positive results in animals outweigh negative epidemiologic results, and

that positive results in one species outweigh negative results in another.

During the 1970s and 1980s, the agencies began using quantitative risk assessments for carcinogens. Today, while there are still considerable uncertainties in quantitative risk assessment,

all the agencies use it. They assume that human

risk estimates can be derived from animal data,

that carcinogenic chemicals lack no-effect thresholds, and that risk estimates should be based on

the most sensitive animal species. All the agencies

use extrapolation models that assume low-dose

linearity, although they differ on the mathematical technique to use, whether the focus should be

on the “upper confidence limit” or “maximum

likelihood estimate, ” and the method to convert

animal doses into human doses. The agency policies do not distinguish chemicals based on their

mechanisms of action and are only beginning to

explore the use of pharmacokinetic modeling techniques.

Agency policies give much less detailed guidance on estimating human exposures to specific

chemicals. Instead, they rely on case-by-case

evaluations. Nevertheless, the lack of detailed

guidelines does not diminish the great importance

of this factor in estimating human risk.

Despite some differences, the approaches of the

regulatory agencies to carcinogen risk assessment

have many similarities. OMB, on the other hand,

has indicated that it does not agree with parts of

the common approach.
Chapter 3

Federal Agency Assessment

and Regulation of Carcinogens
CONTENTS

Page

OSHA Regulatory Actions . . . . . . . . . . . . . . 78

MSHA Regulatory Actions . . . . . . . . . . . . . . 85

FDA Regulatory Actions . . . . . . . . . . . . . . . . 86

Role of Quantitative Risk Assessment. . . 88

Regulatory Actions on Carcinogens in

Foods and Cosmetics . . . . . . . . . . . . . . . 97

Regulation of Animal Drug Residues. . . . 99

Regulation of Carcinogenic Human

Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

CPSC Regulatory Actions .. .. ... ... ... ..103

EPA Regulatory Actions Under the Clean

Air Act . . . . . . . . . . . . . . . . . ... ... ....105

EPA Regulatory Actions Under the Clean

Water Act...... . ..................10 6

EPA Regulatory Actions Under the Safe

Drinking Water Act . ...............112

Drinking Water Standards. . ...........112

Health Advisories . . . . . . . . . . . . . . . . . . ..115

EPA Regulatory Actions Under FIFRA. ...ll7

Actions on Pesticides Already Identified

as Carcinogenic . . . . . . . . . . . . . . . . . . . .118

Other Pending Issues . ................126

EPA Regulatory Actions Under TSCA ....126

New Chemicals . .....................126

Existing Chemicals—Obtaining

Additional Data, . .............,.,,.128

Existing Chemicals—Identified

Hazards . . . . . . . . . ..................131

EPA Regulatory Actions Under RCRA. ...l34

EPA Regulatory Actions Under CERCLA. .l35

EPA’s Carcinogen Assessment Group ., ...138

Office of Management and Budget . ......139

Possibilities for Improving Agency

Timeliness, ....... . ............14 2

Tables

Table

3-7.

3-8.

3-9.

3-1o.

3-11.

3-12.

3-13.

3-14.

3-15.

3-16.

3-17.

3-18,

3-19.

3-20.

Table

3-1.

3-2.

3-3.

3-4.

3-5.

3-6.

No. Page

OSHA Regulation of Carcinogens . . . 80

NIOSH Identification of Carcinogens 83

MESA/MSHA Regulation of

Carcinogens . . . . . . . . . . . . . . . . . . . . . . 87

FDA: Carcinogens Associated With

Foods and Cosmetics . . . . . . . . . . . . . . 89

Potentially Carcinogenic Animal

Drugs Considered for Regulation by

FDA . . . . . . . . . . . . . ................100

Human Drugs Regulated as

Carcinogens by FDA . .............102

3-22.

3-23.

3-24.

No. Page

CPSC Regulation of Carcinogens . . . .104

Carcinogens Considered for

Regulation Under the Clean Air Act .107

Carcinogens Considered for

Regulation Under the Clean Water

Act . . . . . . . . . . . . . . . . . .............108

Classes of Substances Regulated

Under the CWA Consent Decree ....110

Carcinogens Regulated and Proposed

for Regulation Under the Safe

Drinking Water Act, Actions Before

1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113

National Primary Drinking Water

Regulations for Carcinogens, Actions

After 1980. . . . . . . . . . ..............116

FIFRA: I. Canceled and Restricted

Carcinogenic Pesticides. .. ... ... ....120

FIFRA: II. Voluntary Cancellations

of Carcinogenic Pesticides . . . . . . . . . .122

FIFRA: III. Carcinogenic Pesticides in

Special Review:

A. Presently Under Review . ........123

B. Special Review Complete But

Substance Not Suspended or

Canceled . .....................12 4

FIFRA: IV. Pesticides Identified as

Carcinogenic But Not Reviewed or

Canceled . ........................12 5

TSCA: New Chemicals; Section 5

PMN Reviews . ...................127

TSCA: Existing Chemicals;

Testing Required To Determine

Carcinogenicity . ..................130

TSCA: Existing Chemicals Identified

as Carcinogens . . . . . . . . . . . . . . . . . . . .132

TSCA: 4(f) Reviews . ..............133

TSCA: Existing Chemicals;

Significant New Use Rules for

Carcinogens . .....................133

TSCA: Existing Chemicals; Section 6

Actions . .........................13 4

Substances Listed in CERCLA That

Were Identified as Potential

Carcinogens . .....................137

Substances Evaluated by the EPA

Carcinogen Assessment Group for

Carcinogen Potency as of

Aug. 1, 1986 . . . . . . . . . . . . . . . . . ....140
Chapter 3

Federal Agency Assessment

and Regulation of Carcinogens

This chapter describes the major statutes and

agency actions regulating human exposure to carcinogens. Most of these statutes do not single out

carcinogens for specific consideration, but merely

regulate them as a species of toxic substance. The

exception to this is the Food, Drug, and Cosmetic

Act (FDCA), which, in its “Delaney clause, ” prohibits the intentional use of carcinogens as food

or color additives. In the Clean Water Act (CWA),

the Toxic Substances Control Act (TSCA), and

the Resource Conservation and Recovery Act

(RCRA), Congress did not specify any particular type of regulatory action for carcinogens beyond what is required for other toxic effects. But

carcinogens were mentioned as agents of particular congressional concern.

These laws established different regulatory

mechanisms and specified the considerations on

which the agencies are to make regulatory decisions and the range of allowable discretion. Under some provisions of FDCA, TSCA, and the

Federal Insecticide, Fungicide, and Rodenticide

Act (FIFRA), premarket review of a substance is

required before it can enter into commerce. Most

of the statutes, including other provisions of

FDCA, TSCA, and FIFRA, however, provide for

postmarked regulation of substances after they

have been in commerce and people have been exposed to them. Once a health problem has been

identified an agency would be required to either

propose a regulation based on that finding, such

as, under the Clean Air Act (CAA), CWA, the

Safe Drinking Water Act (SDWA), or the Occupational Safety and Health Act, or establish this

fact in court, and seek a judicial remedy on that

basis. Some sections of FDCA and the statutes

administered by the Consumer Product Safety

Commission (CPSC) follow this approach,

To regulate carcinogenic substances, Federal

agencies follow rulemaking procedures that are

set by their statutes or those established by the

Administrative Procedure Act (5 U.S.C. 553),

which may be either informal or formal. Under

the latter procedures the agency must issue a “Notice of Proposed Rulemaking” (NPRM), which

describes the proposed regulation, explains the basis for the proposal, and announces an opportunity for comment by interested parties. After written comments are received, a hearing maybe held

to obtain public comments. After considering the

comments, a final rule is published in the Federal

Register. The proposal may also be altered or

withdrawn. Formal rulemaking procedures differ

from informal ones by the nature of the evidence

presented during the comment period, the opportunity for cross-examination of witnesses in hearings, which may resemble the proceedings in a

court of law, and, some argue, closer scrutiny by

the courts.

The nature of the evidence an agency may consider as the basis for carcinogen regulation reveals

various attitudes toward the acceptability of risk.

In the most general terms, regulatory approaches

are of several types:

● risk-based, such as the Delaney clause of the

FDCA which requires the ban of a food additive shown to cause cancer in humans or

in animal tests;

• technology-based, which might require the

use of “best available technology” (BAT) or

“best practical technology” (BPT) to control

emissions from a particular source; or

● risk-benefit or cost-benefit balancing, which

could permit the consideration of competing

health risks and benefits—such as in the case

of cancer-causing drugs used to treat fatal

illnesses—or the costs of control and other

economic impacts.

There are also different types of agency actions.

Some statutes set exposure standards for air (e.g.,

the Occupational Safety and Health Administra77
78

tion’s permissible exposure limits) or water (e.g.,

exposure limits in water under SDWA). Others

require emission standards for air (under CAA)

or water (under CWA). Under other statutes, Federal agencies issue rules concerning the “safe use”

of a product (under the Consumer Product Safety

Act (CPSA), FDCA, or FIFRA), and some permit

or require outright banning of substances or products containing them (under FDCA, FIFRA-

, and

CPSA). 1 -

Agency actions in trying to control carcinogens

have been as varied as the statutes under which

1This background paper only describes the nature of the standards or regulations issued, and does not discuss implementation and

enforcement of these regulations.

OSHA REGULATORY ACTIONS

The Occupational Safety and Health Act of

1970 established the Occupational Safety and

Health Administration (OSHA) and the National

Institute for Occupational Safety and Health

(NIOSH). OSHA is a regulatory agency which,

among its other duties, issues and enforces regulations that limit exposure to carcinogens in the

workplace. NIOSH is a research agency that has

supported epidemiologic and toxicologic research

and makes recommendations to OSHA concerning changes in occupational health standards.

The act provides three statutory mechanisms

for establishing standards for protection from hazardous substances:

1.

2.

Section 6(a), which authorized OSHA to

adopt the standards already established by

Federal agencies or adopted as national consensus standards, as “startup standards” during the first 2 years after the act went into

effect. The original source for most of these

standards was the list of threshold limit

values (TLVs) published by a professional

society, the American Conference of Government Industrial Hygienists (ACGIH).

Section 6(b), which authorizes OSHA to issue new permanent exposure standards in

rulemaking proceedings.

they work. Some agencies have regulated as many

as 191 potential carcinogens (under the Comprehensive Environmental Response, Compensation

and Liability Act (CERCLA, or Superfund) and

29 carcinogenic chemical classes (of the 65 classes

required to be regulated in a judicial order under

CWA), while others have regulated only a few

(e.g., under the authority of CAA, the Environmental Protection Agency (EPA) has regulated 4

carcinogens in 16 years). For the most part, it appears that the agencies do not act quickly when

they learn that a substance is carcinogenic, since

there is usually a considerable delay between the

time when the outcome of human epidemiologic

studies or animal bioassays becomes known and

final regulations are published, as well as between

the issuing of proposed and final rules.

3. Section 6(c), which authorizes OSHA to issue emergency temporary standards that require immediate action to reduce a workplace hazard when employees are exposed

to a “grave danger. ” A section 6(c) action

also initiates the process of establishing a permanent standard under 6(b).

The standards issued may require monitoring and

medical surveillance, modification of workplace

procedures and practices, requirements for recordkeeping, and new or modified Permissible Exposure Limits (PELs), which are the maximum

concentrations of toxic substances permitted in

the workplace air.

Standards adopted under section 6(b) must

“adequately assure” that “to the extent feasible

. . . no employee will suffer material impairment

of health or functional capacity even if such employee has regular exposure to the hazard dealt

with by such standard for the period of his working life. ” Interpreting this mandate has been at the

center of legal disputes around OSHA’s regulation of toxic workplace exposures. In a major decision, the Supreme Court invalidated OSHA’s

1978 benzene standard, ruling that OSHA had to

demonstrate that exposure at the current permis-
79

sible levels presents a “significant risk” to workers before lower exposure standards can be issued.

Prior to this decision, OSHA had prepared

quantitative risk assessments concerning substances it regulated. The first one of these was prepared in 1976 for the proposed standard regulating coke oven emissions (118). In the case of

benzene, however, OSHA concluded that because

of the uncertainties, it would not conduct quantitative risk assessment. The subsequent legal battle involved whether OSHA would be required

to conduct such assessments. Following the benzene decision, OSHA has conducted quantitative

risk assessments to demonstrate that current permissible exposure levels present a “significant risk”

to workers. The first quantitative risk assessment

conducted after the Supreme Court decision involved worker exposure to arsenic.

In 1971, OSHA adopted exposure limits on approximately 400 specific chemical substances as

startup standards as required by section 6(a). Although these exposure limits had been developed

primarily to protect against noncarcinogenic toxicities, some of the substances are also carcinogens.

From 1972 to 1986 OSHA issued more stringent health standards covering 22 carcinogens (see

table 3-1). Nine of OSHA’s final actions on health

standards established new PELs and other requirements on individual carcinogens (asbestos (1972),

vinyl chloride (1974), coke oven emissions (1976),

benzene (1978), 1,2-dibromo-3-chloro-propane

(DBCP) (1978) arsenic (1978), acrylonitrile

(1978), ethylene oxide (1984), and a second regulation on asbestos (1986)). One OSHA standard

regulating a group of “14 carcinogens” did not institute or change a PEL, but created new requirements for work practices and medical surveillance

for this group of carcinogens and mandated use

of “closed system operations. ”2 One final action

in 1983 clarified that asphalt fumes, which contain known carcinogens, are not regulated under

‘According to OSHA’s preamble to the final rule, 13 of these 14

substances were derived from ACGIH Appendix A. Alpha-naphthylamine was added because it is often found together with betanaphthylamine. Dimethyl sulfate appears in the ACGIH appendix

but was excluded for inadequate documentation of carcinogenicity

(272).

the OSHA startup standard for coal tar pitch volatiles (219). The reason for this is that asphalt fumes

contain a significantly lower percentage of the

polyaromatic hydrocarbons listed in the coal tar

pitch volatile standard (278).

Thus, OSHA has used two different approaches

for limiting exposures: setting permissible exposure limits and requiring specific process technology and procedures. The latter was used for

the group of 14 carcinogens and, while a permissible exposure limit for coke oven emissions was

set, the standard also included relatively specific

requirements concerning the types of engineering

controls that were to be used. For either approach,

OSHA has mandated the use of engineering controls as the primary method of compliance, in contrast to use of gas masks and respirators (219).

The focus on “closed systems” and stringent work

procedures instead of setting PELs for the 14 carcinogens reflected the facts that closed system

operations were possible and that many of these

chemicals had readily available substitutes.

OSHA has also issued “generic” standards that

apply to large groups of chemical exposures. Two

of these affect workers exposed to carcinogens—

the Hazard Communication Standard and the Access to Medical and Exposure Records Standard.

The former requires that hazardous chemicals in

the workplace be labeled, that employers set up

training programs for workers on chemical hazards in the workplace, and that chemical manufacturers prepare and that employers keep copies

of material safety data sheets for hazardous chemicals. The standard defines hazardous chemicals

to include carcinogens (29 CFR 1910.1200).

The Access to Medical and Exposure Records

Standard (29 CFR 1910.20) requires that employers

allow employees and their representatives access

to medical and exposure records and requires that

these records be preserved for specified time

periods. However, the standard does not require

that employers conduct exposure monitoring or

medical surveillance. The standard does require

that if the employer conducts such monitoring or

surveillance that records be kept and made available to workers. Again, exposures to carcinogenic

chemicals are covered by this standard.
80

co

0I
Table 3.1 .—OSHA Regulation of Carcinogens—Continued

Substance Type of evidence

.

Ethyleneimine Animal, 2 species–rats, mice

Ethylene oxide Human, strongly suggestive evidence, animal,

1 species–rats

Formaldehyde Animal, 2 species–mice, rats

Inorganic arsenic Human

Methyl chloromethyl ether Inconclusive–contains bls-chloromethyl ether

4,4- Methylenebw (2-Chloroanlhne)

(M BOCA) Animal, 2 species–rats, mice

alpha- Naphthylamme Found m association with beta-Naphthylamme

& has carcinogenic derivatives

beta-Naphthylamme Human, animal, 5 species–rats, mice,

hamsters, dogs, monkeys

4- Nitroblphenyl Animal, 1 species–dog, forms 4-Ammodlphenyl which IS carcmogemc m humans

beta-Proplolacton e Animal, 3 species–mice, rats, hamsters

N- Nitrosodlmethylamlne Animal, 6 species–rats, mice, rabbits,

hamsters. guinea pigs, fish

Trichloroethylene Animal, 1 species–mice, data inconclusive

Vinyl chloride Human, animal, 3 species–rats, mice.

hamsters

Petition NPRM

— 9-7-73b

8-31-81 (HRG/AFSCME) 4-21-83

10-26-81 (UAW) 12-10-85

— 1-21-75

— 9-7-73 b

— 9-7-73b

2-3-75

. 9-7-73b

1-4-73 (OCAW/HRG) 9-7-73b

1-4-73 (OCAW/HRG) 9-7-73b

1-4-73 (OCAW/HRG) 9-7-73b

1-4-73 (OCAW/HRG) 9-7-73b

— 10-20-75

3-14-74 (UnNed Rubber Workers, 4-5-74(1)

IUD. OCAW)

. . .

Final Court action challenge

1-29-74 ‘‘Fourteen Carcinogens’ ‘a

6-22-84 HRG et a/ v Auchfef 554 F Supp 242

(D C DISt Ct 1-5-83) & 702 F 2d 1150

(D C Cir 3-15-83)

— —

5-5-78 Affirmed, ASARCO Inc. et al v OSHA 746

F 2d 483 (9th Cir 9-13-84)

-29-74 “Fourteen Carcinogens’ ‘a

-29-74 ‘Fourteen Carcinogens a

–vacated 12-17-74

-29-74 ‘Fourteen Carcinogens’ ‘a

I

1-29-74 ‘ ‘Fourteen Carcinogens’ ‘a

1-29-74 ‘‘Fourteen Carcinogens’ ‘a

1-29-74 ‘‘Fourteen Carcinogens’ ‘a

1-29-74 ‘‘Fourteen Carcinogens’ ‘a

—

10-4-74

—

Affirmed, Society of the Plastics Industry Inc

v OSHA, 509 F 2d 1301 (2d Cir.

1-31-75) I

astanda~d~ were i~~ued ~lmujtaneously for 14 Carcinogens Inltlally Issued as emergency temporary standards 2 of the 14 were struck dow~’ In Dry Color ~anufacturln9 v Dep~timent of Labor, 486 F 2d 98

(3rd Clrcult. Oct 4, 1973) Final standards were then Issued The Court upheld all final standards except 44 Methylenebls (2.chloroanlllne) In SYntheflc Organic Chemlca/ Manufacturers .Assoc/at/on v Brennan

506 F 2d 385 (3rd Circuit. Dec 1 i’, 1974) The ethylenelmlne standard was affirmed In SYnfhetlc organic Chernfca/ Manufacturers Assoclatfon v Brerrnan, 503 F 2d 1155 (3d Clr 8.26-74)

bAlso an emergency temporary standard

SOURCES. OSHA response to OTA request, Federal Regwter notices cited In the agency response, Preventing Illness and Injury In the Workplace, OTA, 1985, “Summary of OSHA Regulations & NIOSH Recoin

mendatlons for Occupational Safety & Health Standards, 1986” publlshed in MMWR VOI 35, No 1S

co

I
82

Both standards are important. The Hazard

Communication Standard, in particular, has led

to a major effort devoted toward updating material safety information and communicating this

information to workers. In addition, OSHA is

now in the process of expanding the scope of the

Hazard Communication Standard to all industries. The standard currently applies to the manufacturing sector, including chemical companies

that supply the relevant hazard information, but

nonmanufacturing industries are not required to

implement the program. The effects of these

standards on actual exposures in the workplace,

however, are indirect. OSHA is still working on

standards setting specific exposure levels and mandating other types of health and safety activities,

even for chemicals covered by the Hazard Communication and Access to Records standards.

OSHA’s regulation of carcinogens has been

controversial. Of nine final actions on individual

carcinogens, seven have resulted in court challenges: on asbestos (twice), vinyl chloride, coke

oven emissions, benzene, arsenic, and ethylene

oxide. The rules on DBCP and acrylonitrile were

not challenged as final standards. For the standard regulating 14 carcinogens as a group, the

ethyleneimine and 4,4-methylenebis( 2-chloroaniline) (MBOCA) standards were challenged. In all,

two permanent standards were struck down as a

result of those challenges: MBOCA and benzene.

Thus, standards are in effect for 20 of the 22 chemicals regulated as carcinogens.3

In the 16 years since the OSH Act passed,

NIOSH, part of the Centers for Disease Control,

issued 93 recommendations concerning carcinogens. As summarized in table 3-2, these consisted

of 32 criteria documents, 6 revised criteria documents, 19 current intelligence bulletins, 10 special hazard reviews, 3 health hazard alerts, 1 occupational hazard assessment, and a list of 22

substances (including the “14 carcinogens”) for

which recommendations were made in testimony

presented in 9 OSHA regulatory proceedings. Criteria documents and regulatory testimony identify substances that pose potential health problems and recommend exposure levels to OSHA.

3A recent report of the Administrative Conference of the United

States discusses OSHA rulemaking. See (1).

The other documents represent NIOSH efforts to

communicate research findings and warnings to

workers and employers.

NIOSH has changed its policy on criteria documents. While a large number were produced in

the early to mid-1970s, OSHA criticized the quality of the documents and rarely responded (see

table 3-2). Starting under NIOSH Director Anthony Robbins, the agency placed greater emphasis on epidemiologic studies and health hazard

evaluations (evaluations of reported worker

health problems in particular workplaces), and

has reemphasized production of criteria documents. From 1971 to 1980, NIOSH issued 77 recommendations, about 7.7 per year, while from

1981 to 1986, it has issued 16 criteria documents,

current intelligence bulletins, or special hazard

alerts, about 2.6 per year.

In all, the NIOSH recommendations cover 71

different chemicals or processes that were determined by NIOSH to be carcinogenic. Of these 71,

OSHA has responded by issuing health standards

for 21 chemicals or processes: asbestos (twice),

arsenic, coke oven emissions, vinyl chloride, benzene, acrylonitrile, ethylene oxide, and the 14 carcinogens regulated together. However, for two

chemicals (benzene and MBOCA), the OSHA

standard was vacated by the courts. Thus 19

chemicals and processes have actually been regulated for carcinogenic effects based on NIOSH

recommendations. OSHA regulated one chemical, DBCP, for carcinogenic effects although the

NIOSH recommendation was only based on adverse toxic effects. As of early 1987, OSHA has

an active proposal pending on benzene exposures.

However, no activity is currently being considered for MBOCA exposures, although this substance is still being imported and used in the

United States.

The remaining sO chemicals or processes have

not been the subjects of final OSHA 6(b) standards, although many are being regulated under

6(a) standards that were adopted in 1971 based

on recommendations concerning noncarcinogenic

effects. Of these 50 chemicals or processes, OSHA

has proposed regulations for 4: formaldehyde,

ethylene dibromide, trichloroethylene, and beryllium, although the latter two were proposed in
83

Table 3-2.—NIOSH Identification of Carcinogens

Type of OSHA proposed

Substance recommendation Date or final action Type of evidence

2-AcetyIaminofluorene . . . . . . . . . . . . . . . . . . . .

Acrylonitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Aldrin/Dieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . .

4-Amlnobiphenyl . . . . . . . . . . . . . . . . . . . . . . . . .

Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Arsine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzidine-based dyes . . . . . . . . . . . . . . . . . . . . .

Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

bis-Chloromethyl ether . . . . . . . . . . . . . . . . . . . .

l,3-Butadiene . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Carbon black . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Carbon tetrachloride . . . . . . . . . . . . . . . . . . . . . .

Chloroform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chloroprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chrysene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Coal gasification plants . . . . . . . . . . . . . . . . . . .

Coal liquefaction . . . . . . . . . . . . . . . . . . . . . . . . .

Coal tar products . . . . . . . . . . . . . . . . . . . . . . . . .

Coke oven emissions . . . . . . . . . . . . . . . . . . . . .

DOT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,4-Diaminoanisole . . . . . . . . . . . . . . . . . . . . . . .

3,3’- Dichloro-benzidine. . . . . . . . . . . . . . . . . . . .

Di-2-ethylhexyl Phthalate (DEPH) . . . . . . . . . . .

4-Dimethylaminoazobenzene . . . . . . . . . . . . . . .

Dinitrotoluenes . . . . . . . . . . . . . . . . . . . . . . . . . .

Dioxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene dibromide . . . . . . . . . . . . . . . . . . . . . . .

Ethylene dichloride . . . . . . . . . . . . . . . . . . . . . . .

Ethyleneimine . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene oxide... . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene thiourea. . . . . . . . . . . . . . . . . . . . . . . . .

Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Foundries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Glycidyl ethers. . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachloroethane . . . . . . . . . . . . . . . . . . . . . . . .

Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

T

CD

SHR

T

CD

CD(rev)

CIB

CD

CD(rev)

T

CD

CD(rev)

T

T

T

SHR

CD

T

T

CIB

CD

CIB

CD

CD

CD(rev)

CD

CD (rev.)

CD

CD

SHR

CD

OHA

CD

CD

T

SHR

CIB

T

SHR

T

CIB

CD

CD

CIB

CD

T

CD

CD(rev)

T

SHR

T

SHR

CD

CIB

T

CD

CD

CIB

CD

9-73

9-77

9-78

9-73

9-74

6-75

8-79

1-72

12-76

6-84

7-74

8-76

7-77

3-86

9-73

11-79

6-72

8-77

9-73

2-84

8-76

9-84

9-78

12-75

6-76

9-74

6-76

8-77

12-75

6-78

9-78

3-81

9-77

2-73

11-75

9-78

1-78

9-73

3-83

9-73

7-85

9-77

9-76

10-78

8-77

11-83

3-76

9-78

9-73

9-77

7-83

10-78

12-76

4-81

5-86

985

6-78

8-78

6-78

1-29-74

10-3-78

—

1-29-74

—

5-5-78

—

1-21-75”

—

6-20-86

—

—

2-10-78**

12-10-85*

1-29-74

—

10-17-75”

—

1-29-74

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

10-22-76

—

—

1-29-74

—

1-29-74

—

—

—

—

—

—

—

—

1-29-74

—

6-22-84

—

12-10-85’

—

—

—

—

—

Animal

Animal, human

Animal

Human

Human (nonconclusive)

Human

Humana

Human

Human

Human

Human (limited evidence)

Human

Human

Human

Human

Human

Animal

Animal, human

Human

Animal, human

Human (toxic effects)

Animal, human

Animal

Animal

Animal

Animal

Animal

Human

Animal, human

Animal

Animal, human

Animal, human

Animal, human

Human

Animal

Animal

Animal, human (suggestive

evidence)

Animal

Animal

Animal

Animal

Animal

Animal

Animal, human

Animal

Animal

Human (toxic effects)

Animal

Animal

Human (potential)

Animal, human

Animal

Human (toxic effects)

Animal

Animal

Human

Animal

Animal

Animal

human (potential)

continued on next page
84

Table 3-2.—NIOSH Identification of Carcinogens—Continued

Type of OSHA proposed

Substance recommendation Date or final action Type of evidence

Isopropyl alcohol . . . . . . . . . . . . . . . . . . . . . . . . .

Kepone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methyl chloromethyl ether. . . . . . . . . . . . . . . . .

4,4’ -Methylenebis-(2-chloroaniline) (MOCA) . . .

Methylene chloride . . . . . . . . . . . . . . . . . . . . . . .

4,4-Methylenedianiline . . . . . . . . . . . . . . . . . . . .

Monohalomethanes . . . . . . . . . . . . . . . . . . . . . . .

alpha-Naphthylamine. . . . . . . . . . . . . . . . . . . . . .

beta-Naphthylamine . . . . . . . . . . . . . . . . . . . . . .

Nickel carbonyl . . . . . . . . . . . . . . . . . . . . . . . . . .

Nickel, inorganic compounds . . . . . . . . . . . . . .

4-Nitrobiphenyl . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Nitronapthalene . . . . . . . . . . . . . . . . . . . . . . . .

2-Nitropropane . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-Nitrosodimethylamine . . . . . . . . . . . . . . . . . . .

O-Dianisidine-based dyes . . . . . . . . . . . . . . . . . .

O-Tolidine-based dyes. . . . . . . . . . . . . . . . . . . . .

O-Tolidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenyl-beta-naphthylamine . . . . . . . . . . . . . . . .

Polychlorinated biphenyls . . . . . . . . . . . . . . . . .

beta-Propiolactone. . . . . . . . . . . . . . . . . . . . . . . .

2,3,7,8-Tetrachloro-dibenzo-p-dioxin (TCDD) . .

1,1,2,2-Tetrachloro-ethane . . . . . . . . . . . . . . . . . .

1,1,2,2-Tetrachloroethane . . . . . . . . . . . . . . . . . .

Tetrachloromethylene . . . . . . . . . . . . . . . . . . . . .

Trichlorethylene. . . . . . . . . . . . . . . . . . . . . . . . . .

1,1,2-Trichloroethane. . . . . . . . . . . . . . . . . . . . . .

Vinyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vinyl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CD

CD

T

T

SHR

C D

CIB

CIB

T

T

SHR

CD

T

CIB

HHA

T

HHA

HHA

CD

CIB

CD

T

CIB

CD

CIB

CD

CIB

CD

SHR

CIB

CD

CIB

3-76

1-76

9-73

9-73

1978

3-76

4-86

7-86

9-84

9-73

9-73

5-77

5-77

9-73

12-76

4-77

10-80

9-73

12-80

12-80

1-74

10-76

9-77

9-73

1-84

12-76

8-78

7-76

1-78

6-73

1-78

8-78

3-74

9-78

—

1-29-74

1-29-74**

2-3-75* —

—

1-29-74

1-29-74 —

1-29-74

1-29-74 —

—

—

—

1-29-74

—

—

—

1O-2O-75* no

final action

10-20-75” —

10-4-76 —

Humanb

Animal

Animal

Animal

Animal

Human (toxic effects)

Animal

Animal, human

Animal

Human

Human

Animal

Animal, human

Animal

Animal (caused by metabolite)

Animal

Animal

Animal

Animal, humane

Animal, humane

Animal

Animald

Animal

Animal

Animal

Animal, human (toxic effects)

Animal

Human (toxic effects)

Animal

Human (toxicity data)

Animal

Animal

Animal

Animal. human

*Date of notlce of proposed rulemaking (NPRM)

* *Vacated

agased on evidence for arsenic because Arsine metabolizes to inorganic arSeniC in the human body.

bcarcinogenlc effect con~idereddedved from Strong.acid In production process, no evidence for carcinogenicity of iSOprOpyl alcohol itSelf.

Cgased on evidence for benzidine because it converts to benzidine itl humans.

dgased on evidence for beta.naphthylamine because it metabolizes to beta-naphthylamine in humans,

ABBREVIATIONS. CD = Criteria Document, CIB = Current Intelligence Bulletin; HHA = Health Hazard Alert, OHA = Occupational Hazard Assessment; (rev) = Revised, SHR = Special Hazard Review; T = Testimony to Dept. of Labor

SOURCES: NIOSH/OSHA responses to OTA request including summary of NIOSH Documents for Carcinogenic Agents; “Summary of OSHA Regulations and NIOSH

Recommendations for Occupational Safety and Health Standards,” 1986, published in MMWR vol. 35, No 1S; Preventing Illness and Injury in the Workplace,

OTA. 1985.

1975 and can now be considered dormant. For the

remaining chemicals or processes, no OSHA proposals have been issued.

OSHA’S regulatory agenda has increasingly

been set by outsiders, through petitions, court

orders, referrals from EPA and congressional

directives. The formaldehyde standard involved

a petition, a referral from EPA and a court order

after OSHA delays. OSHA has also received formal or informal referrals from EPA under section

9 of TSCA, for 4,4’-methylene dianiline (MDA),

1,3-butadiene, chloromethane, MBOCA, toluenediamine, glycol ethers, acetaldehyde, and

acrylamide. In the Superfund amendments of

1986, Congress directed OSHA to issue standards

on health and safety protection for workers at

hazardous waste sites.

During the first 10 years of its existence, OSHA

issued 8 final rules, while from 1981 to 1986,

OSHA has issued 2 final rules to reduce exposures

to specific carcinogens, a rate of 3 years per regulation. On average, 15 months have elapsed be-
85

tween OSHA’s issuance of an NPRM and publication of a final rule on a particular substance.

Further, during the first 10 years of OSHA’s existence, the time from criteria document to final

rule was about 32 months, while during the last

6 years, the average has been about 60 months.

There are still a number of regulations yet to be

acted on that could modify this last average,

which is based on just two final rules. One final

rule issued since 1981 was a more stringent regulation of asbestos, previously regulated by OSHA,

while the final rule for ethylene oxide was issued

under court order (see the discussion of judicial

action in app. A). Benzene, first identified as a

health hazard by NIOSH in a criteria document

in 1974, was initially regulated in 1978. That final rule was overturned by the Supreme Court

in 1981. Subsequently, NIOSH has issued several

revised recommendations (in 1976, 1977, and

1986), but OSHA has yet to issue a final rule on

benzene.

Although OSHA’s cancer policy permits the

regulation of carcinogens on the basis of animal

MSHA REGULATORY ACTIONS

The Mine Safety and Health Administration

(MSHA) regulates the exposure of miners to carcinogens. The Federal Mine Safety and Health

Amendments Act (1977) consolidated the regulation of mine health and safety under one statute, and transferred responsibility from the Department of the Interior to the Labor Department.

Safety and health in coal mines had previously

been regulated under the Federal Coal Mine

Health and Safety Act of 1969 by the Department

of the Interior’s Mining Enforcement and Safety

Administration (MESA), while safety and health

in metal and nonmetal mines had been regulated

by MESA under the Federal Metal and Nonmetallic Mine Safety Act of 1966 (150).

Separate standards are issued for surface and

underground coal mines and for surface and

underground metal and nonmetal mines. For the

most part, standards adopt the 1972 and 1973 recommendations of the ACGIH. Other than in radiation and asbestos, MSHA has found relatively

few exposures to carcinogens in mines.

evidence alone, for the most part the agency has

regulated on the basis of human evidence, evidence which in most cases was confirmed by animal evidence. Not considering the 14 carcinogens

regulated as a group, OSHA has issued final rules

for 8 individual substances based on at least some

evidence of human carcinogenicity. DBCP, however, was regulated primarily because it caused

infertility in men, although animal carcinogenicity data was available.

Of the “14 carcinogens, ” 3 are human carcinogens, 8 are positive in 2 or more species (a number of these 11 carcinogens are positive in 3 to

5 mammalian species), and 1 was positive in a single species. The remaining 2 chemicals (alphanapththylamine and methyl chloromethyl ether)

are found in association with other carcinogens

on the list of 14 and were themselves thought to

pose potential risks. Thus 11 of the 22 chemicals

were regulated based partly on human evidence,

and most of the animal carcinogens were regulated early in OSHA’s history—in the 1974 standard on 14 carcinogens.

When MSHA’s predecessor agency issued the

surface coal mining regulations in 1972 it specified that exposures to toxic substances should not

exceed those recommended by ACGIH in 1972.

At that time only some potential carcinogens in

diesel fumes and polychlorinated biphenyls

(PCBS) were thought to present possible problems

in the surface mining of coal.

For underground coal mining, MSHA’s regulations require mines to keep exposures at least

as low as the “current” ACGIH recommended exposures, with the idea that the exposure levels

would be updated each time ACGIH changed its

list of toxic substances. Although MSHA legal

staff interpret “current” to be the 1972 list, which

was current when the regulations were issued,

MSHA staff stated to OTA that inspectors enforce

those that are actually current. The issue has not

been resolved in part because there have been very

few citations. There is debate within the agency

over whether it would be in violation of the

Administrative Procedure Act for the regulations
86

to be automatically updated by ACGIH because

it would not provide opportunity for the public

to comment on the updated exposure levels (190).

Regulations that govern exposure to carcinogens in metal and non-metal mines incorporate

by reference the 1973 ACGIH recommendations.

In 1978, for metal and non-metal mines, MSHA

regulated the 14 carcinogens that had been regulated by OSHA in 1974, and 2 other substances,

by restricting their use to approved laboratory

conditions and competent personnel (see table 3-3).

Apart from incorporating by reference the

ACGIH list of carcinogens, MSHA issued regulations in the late 1970s on asbestos, lowering the

permissible exposure level as specified in the 1973

ACGIH list froms fibers to 2 fibers greater than

5 microns in length per cubic centimeter of air

(161). The regulations applied to metal and nonmetal mines and surface coal mines. There are no

regulations however governing exposure to asbestos in underground coal mines. Finally, MSHA

has regulated exposure to radon daughters and

ionizing radiation (1969) and updated these standards once (1976) (see table 3-3).

Following a petition and a lawsuit filed by the

Oil Chemical and Atomic Workers Union and the

Health Research Group for a more stringent emergency temporary standard, and in response to a

court order, MSHA has also proposed to revise

the standards for radiation exposure to uranium

miners (269). The proposed new standard is 4

working level months (WLM) which results in a

cumulative lifetime exposure of 120 WLM over

a 30-year period.4 This standard is similar to the

4A working level refers to a specified concentration of radon

daughters in the air. A working level month is defined as the exposure to one working level for 170 hours. The commonly used doseequivalent of 1 WLM is approximately 1 rem or 4.8 WLM = 5 rem

(a rem is a measure of absorbed dose).

FDA REGULATORY ACTIONS

existing standard except that it also establishes a

combined exposure limit for radon daughters,

gamma radiation, and thoron daughters. Previously, thoron daughters were excluded from coverage altogether.

These standards merit special attention because

uranium miners receive relatively high levels of

radiation exposure compared to other nuclear

workers and have high rates of occupational mortality (119). Radiation protection standards in general are based on the principle that exposures

should be kept “As Low As Reasonably Achievable” (ALARA) (269). The proposed standard is

consistent with the Federal Radiation Guidance,

which is based on the recommendations of the International Commission of Radiological Protection (ICRP). A recent NIOSH evaluation however

found a significant excess of lung cancer deaths

from cumulative radon daughter exposures well

below 100 WLM and concluded that a standard

of 1 WLM a year is achievable (252). NIOSH is

in the final stages of preparing a criteria document

recommending a permissible exposure level.

Increased use of diesel engines in mines has

raised concern about mine worker exposures to

those fumes. Although MSHA routinely samples

and regulates gaseous diesel emissions in accordance with the 1972 and 1973 TLVs, these are not

based on carcinogenic effects. There is no standard regulating particulate diesel emissions except

the limit on respirable dust, which also does not

take into account carcinogenic effects. Finally, in

1986 OSHA revised its standard for asbestos. It

is not clear whether MSHA will take additional

action on regulating exposures to radiation, diesel

fumes, or asbestos.

Carcinogens in foods and cosmetics are regu- gest history. Its requirements have evolved over

lated by the Food and Drug Administration (FDA) time. Prior to the 1950s, the statutory approach

under the FDCA. Of the regulatory statutes con- was to prohibit the sale of adulterated food. Food

sidered in this report, this act has by far the lon- was considered adulterated if FDA could show
87

Table 3-3 .—MESA/MSHA Regulation of Carcinogens: Metal & Non-Metal Mines, Underground & Open Pit

(other than coal), Sand, Gravel, and Crushed Stone Operations, Including Uranium Mine Radiation Standards

— —— --— ——

Adoption of 1973

ACGIH recommendations Revisions a

Substance

Asbestos

bis-(Chloromethyl) ether

Chromates

Coal tar pitch volatiles

Nickel carbonyl

4-Aminobiphenyl (P-xenylamine)

Benzidine & Its salts

Beta -naphthylamine

4- Nitrodiphenyl

Beryllium

Chloromethyl methyl ether

3,3’ -Dichlorobenzidine

Dimethyl sulfate

Ethylenimine

44 -Methylene bis (2-chloraniline)

N-Nitrosodimethylamine

beta-Propiolactone

2-Acetylaminofluorene

Carbon tetrachloride

4- Dimethylaminoazobenzene

Alpha-naphthylamine

Phenol

Uranium mining radiation exposure standards:

NPRM Final Evidence NPRM Final Basis

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

8-29-73

——

—

.

Type of radiation NPRM

Radon daughters 1-16-69 g

6-24-70

9-25-75

Gamma radiation 1-28-77

Radon & thoron daughters and

gamma radiationl

12-19-86

— —

7-1-7 4

b

7-l-7 4

b

7-1-7 4

b

7-1-7 4

b

7-1-7 4

b

7-1-74 C

7-1-74 C

7-1-74 C

7-1-74 c

7-1-7 4

d

7-1-7 4

d

7-1-74°

7-1-74°

7-1-7 4

d

7-1-7 4

d

7-1 -74”

7-1 -74*

—

—

—

—

—

Final

Human

Human

Human

Human

Human

Human

Human

Human

Human

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

—

—

7-7-77

7-7-77 —

—

—

7-7-77

7-7-77

7-7-77

7-7-77 —

7-7-77

7-7-77 —

—

7-7-77

7-7-77

7-7-77

7-7-77

7-7-77

7-7-77

7-7-77

7-7-77

11-17-78

11-17-78

—

—

—

11-17-78

11-17-78

11-17-78

11-17-78

—

11-17-78

11-17-78 —

—

11-17-78

11-17-78

11-17-78

11-17-78

11-17-78

11-17-78

11-17-78

11-17-78

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

—

OSHA Standard

OSHA Standard

OSHA Standard

OSHA Standard

P

OSHA Standard

OSHA Standard

Basis Court challenge/ petitions

2-25-70 FRC Guidance, 1967

12-8-70 –

6-10-76 EPA Guidance 5-25-71

(dewed from FRC

recommendation 1 -15-69)h

6-8-77 NCRP/lCRP recommendations

— ICRP 26 4-21-80, Petition (OCAW /HRG) for 1 7

WLM/yr ETS 3-13-84 OCAW & Public

Clitizen HRG v David Zeeger, 768 F 2d

1480, (D C. Cir 8-2-85): 1-29-85 denied

ETS. issued ANPRM

‘Jn the revlsea regulations excepl for asbestos for h h!ch the e ~ PDSI, ’? Im It ,t ,3> rtfll]ced I LI S H h

reslrlcled the use of the ,Islec substances [O a~pro, ed Iabo ‘~lo’ Y “ IJr CII CIr r Y

 - ~mnelenl :Ier son

nel The IIS1 was uased on Iechnlca and medical e~ldeoce : OIMOI ea b Y CI SHA for tne regulaltor~

ot Ce-laln carcinogens Accoralng to MSHA however most If ncl al Cf Iho Ihslea chemcals are

seldom d ever used In foe mineral mdustnes $oblecf to IOe Metal anc ‘,onmelal Lllne Satety Act

DRegulaflon conslsls Of ~CGIH TL J

C.ACGI H CIC not Issue ? TLU regulation ddopls ACGIH ‘ecommendallon lhal PO exposure or contact

be perm[tled

dACGIH d,d no[ ,~~ue , ‘LV reqblat on ado~l~ ACG/H recommenca{lon that exposure should be reducea

10 a minimum

ef’arbon tetrachlorl~e ,$ds ,~~(~deg ~n [he I(sf Of restricted chemicals e,en though 11 was not fegu

Ialed as a carcinogen bf OSHA It hao alreac~ been promulgated as a mandator! slanaarc b) MSHA

according to Info< mallon proi ldec II response 10 the OTA recuesl I Agerda 10 91h Annual Meeting I

but there IS no lnd(c,?lon w her ‘h IS occJr’ed

lphenol ~a5 !Is[ed for acute IOXICII) and because I! IS a susoect Carclnoqen ~Gcofdng 10 NIOSH even

lhoJgh f was not ‘egulaled oy OSHA

9p,lor 10 the 197o tlnal s[anaa,as heallh and safef~ n uran{um mnes has regu afed by the %2tU

Several Federal agenc(es pro~aed advice and assistance and formed an mterageocy commlltee but

helc that IFIF , I :r, cc the proper statutory authorlly 10 regulate radlatlon exposure r Dr vafelj OA ned

11 $,1 ,) 11 11 Int . I r 1 (1 ’,1-1 lh~ I.I S Publ(c Health service began 10 Invesllgale Ihe Ie, els of r~d dl)o!l

e.pl,~~,re :nfi lhIe h~, j ‘h ~,t’erfs of uranwm mlmng al the request 01 the Colorado hea’<h depart

rltint I n “ QI~ I h? Atcll II E ]erg) Commlsslon dtd begin to respect mines and m}l Is on Feder,i I

Iancs dr d rec~) rc 3 I iI \ ,,:, r cmpllance wllh [he 1957 radlahon slanaaros By dolog SIO Ihk A E C

demoostrafed tfle ‘e~s I: II II, 21 controlling radiallon Ie’(ek m mines which prompted the mler~qenr ,

COMMlflW[c c or. crl~. 3 “ Jnferente of governors f“OM Uramum mlmng Slates and representafl, es

of the con :ernec Feder,il jq:l(Ie$ on Dec .2 1960 11 was al this meeftng lhz! fhf? USPHS re

po-tec prelmwr,d]l I sh~~nq fhdl uramum mmers had a lung cancer rate 5 f(mes hgher tnan

the U S while male pooulalc r

fllhe lgfjl FRC I Federal Radiaflon COUM I ,econlnjendallons were baseo on the recommendations

of the NCRP ( Nabonal Comm(sslcl cn P ~aolo~ IL dl Prolec.!lon I The revised 1969 E RC recommend

lions were based on a NAS repcrl prep~red for I he I n!erzgency Uramum Mining Radiation Re, ci,

Group (IUMRRGI enhlleo Eo!denl(ol:{jr Sf]dws of Ur?rwm Mlne~s which recogmzed dn lncreasec

Incidence of lung cancer at 1,X 3’ ‘~ I: LI II I Ml , & ‘WL M

‘The exlslmg rad!allon exposu=? sfan ti,; rc. I: ,er orll i rador daughters and gamma radlaf, on 10 II r

derground mines The NPRM f;r IF.!1 jr Iarcs dlso includes lhoron daughters

SOURCES MSHA response 10 UTA recuesl Inclualng Federd/ Reglsff?r ‘lclI:ssand agenda for the 19th Meeting of the Federal Metal & t~or ),!eI,.I V me Safef, Am sor) Commlflee June 29 30 and J UIj

1 1976 M SHA JOCIZI nq ?aalat(on Standards for Metal 8 !,on Metal M nes -- Preproposai Orafl November 1985 Comments OP MSHA Preprososal Draft submitted by Pubhc Ctizen Heallh

Research Group I HRG a~o Ihe 011 Chemlca( aqd Atomic Workers Infernal(onal Union 10CAWI Feb 18 1986 SOulhwe51 Research & irl~orma[m Ce~i~ IN/OSH Eialuahon of Ewoemm\~9)c

Slud,es Ex~rrln ng :be I ung Cancer Modal,lj of UnCe ”grolJnc! M{lers prepared for MSti A 5986 George T Mazuzan and J Samuel Walker C onlrr,l Of lhe Alonl Unl kecsll~ of C,il(t?-nla

Press 1982
88

that it was “ordinarily injurious to health” or that

it contained an added substance that “may render it injurious to health” (section 402(a)(l)).

Starting in 1954, Congress enacted special statutory provisions for particular groups of substances that might be added to foods or cosmetics,

first, pesticide residues (in 1954, now regulated

by EPA), then food additives (1958), color additives (1960), and animal drug residues (1962).

A “food additive” is any substance, the intended

use of which leads it to become a component of

food either directly or indirectly. The 1958 Food

Additives Amendment established a premarket

approval process for food additives, although excluded from this are substances “generally recognized as safe” (GRAS) and substances that had

received Federal sanction prior to 1958 (“prior

sanction” substances). Food additives include substances used to alter the taste or composition of

food, and packaging materials that may migrate

into the food.

To approve a food additive, FDA must be convinced of the safety of the additive. On this point,

the well-known “Delaney clause” provides “that

no additive shall be deemed to be safe if it is found

to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal.”

For “unavoidable contaminants” found in food

(such as aflatoxins in peanuts, mercury in fish,

and PCBs in milk and fish), the FDA may set tolerance levels through formal rulemaking procedures. Alternatively, FDA has used more informal “action levels, ” which are established without

going through rulemaking. Because they are not

regulations, action levels are easier to change than

tolerances. Action levels and tolerances are both

levels of a contaminant which, if exceeded, would

render the food “adulterated” and lead FDA to

bring court action to seize the foods

FDA’s regulation of carcinogens was affected

by an important case, Monsanto v. Kennedy

(129), which involved a plastic bottle that FDA

‘The authority to establish tolerance levels for pesticide residues

on raw agricultural products was transferred to EPA in 1970 and

will be discussed under the regulation of pesticides.

believed might release a suspected carcinogen into

its contents and thus present a risk to consumers.

The court ruled that FDA need not determine that

a substance was a food additive based on a theoretical prediction of migration, although this is

permissible if there is a safety concern. The court

then went on to declare that FDA could exempt

small amounts of substances in “de minimis situations” that “clearly present no public health or

safety concerns. ” A 1984 court decision, Scott v.

FDA (184), specifically supported FDA’s decision

to allow the use of color additives that contain

carcinogenic impurities, when FDA believes such

use represents an insignificant risk. As discussed

below, FDA has started to apply this by approving certain color additives even though they contain known carcinogens, arguing that the risks are

insignificant.

As a result, FDA’s carcinogen regulation has

changed. Prior to 1982, food and color additives

that contained carcinogenic impurities (formerly

called “constituents”) were banned, but since then

the policy for such impurities is that, if a food or

color additive itself does not cause cancer, but an

impurity of the additive is a known carcinogen,

the agency will use risk assessment to determine

whether “under the general safety clause, there

is a reasonable certainty that no harm will result

from the proposed use of the additive” (245).

Role of Quantitative Risk Assessment

Over time, FDA has given quantitative risk

assessment more importance. The first uses of

quantitative risk assessment were for carcinogenic

chemicals not subject to the Delaney clause. In

1973, FDA proposed to use risk assessment to

specify the sensitivity of the analytic method used

to determine the level of potentially carcinogenic

animal drug residues (see ch. 2). The next application was for setting tolerances and action levels

on food containing unavoidable environmental

carcinogenic contaminants. The first uses of risk

assessment for such contaminants appear to have

been for aflatoxins in 1978 and PCBS in 1979 (table 3-4). In 1982, it was applied to carcinogenic

impurities in color additives, which were not

regarded as subject to the Delaney clause under

FDA’s impurities policy. Finally, risk assessment
Table 3-4.—FDA: Carcinogens Associated With Foods and Cosmetics

— —

Substance When identified Type of evidence Petition ‘NPRM Final Type of action/co=ment~

Acrylonitrile–as contaminant of 6-22-80, 11-24-81 risk Human, respiratory only 3-483 (Monsanto) NA 9-19-84 The agency had revoked all beverage

acrylonitrile/styrene copolymer assessment animal, 1 requesting rule for container uses of acrylonitrile

resin in the manufacture of species–rats safe use polymers 9-23-77 Action in 1984

beverage bottles allows its use based on new

agency policy and development of

a bottle with lower contaminant

Ievels a

Aflatoxin 1-19-78, risk

assessment

Human, animal

2-Aninoanthraquinone 2-21-80 — —

4-Aminoazobenzene

–in FD&C Yellow No 5 12-20-83, risk Animal, 1 species-rats 3-27-65

assessment

—in FD&C Yellow No. 6 — — 11-20-68

12-6-74, proposed –

tolerance 15 ppb in

peanut products,

3-3-78, reopened

comment period

—

—

—

4-Aminobiphenyl

—in Ext. FD&C Yellow No. 1 1954 evidence cited Human, animal, 1 11-23-76, received 9-23-76

species–dogs comments about

substance as

contaminant of azo

dyes

—in FD&C Yellow No. 5 12-20-83, risk

assessment

— 3-27-65

12-20-83, risk — —

assessment

–in FD&C Yellow No. 6 — — 11-20-68

—

9-4-85

—

—

—

9-4-85

11-19-86

12-13-77

9-4-85

7-7-86

11-19-86

—

—

In 1965 aflatoxin contaminated foods

were declared adulterated at the

detection limiat of 30 ppb In 1969

the level changed to 20 ppb which

remains as the current action

Ievelb

Hypothesized Impurity in several color

addiatives; not found

FD&C Yellow No. 5 permanently

listed for use in cosmetics and

externally applied drugs; contains

4-aminoazbenzene impuritya

Permanently listed Yellow No.6.

contains 4-aminoazobenzene

impurity a

Terminated provisional listing of color

additive for use in externally

applied drugs and cosmetics

because of possible benzidine

impurity and 4-aminobiphenyl

impurity

Permanently listed Yellow No. 5 for

use in cosmetics and externally

applied drugs; contains

4-aminobiphenyl impuritya

Adopted uniform specifications,

including specifications on

Impurities for all uses of Yellow

No. 5

Permanently listed Yellow No. 6;

contains 4-aminobiphenyl impuritya

4-Amino-2-nltrophenol 4-29-80 — — Coal tar hair dye ingredient

2-Amino-5-nhro-thlazole 1-8-79 Animal, 1 species–rats – Metabolize of animal drug;

manufacturer withdrew drug from

market after notified about

carinogenic metabolite by FDA

dT~e ,ule5-for ~afe ~,e ~,e ~J~e~ ~r, ~ . 98: i-ou~~ cjec,~,~r, ~h~t ,~llowe~ s~fe pXpOSU ‘e levels [O De es[aolljhed for non carcinogenic ad;lt(ves I hat CO fltdln CdrClflOgefllC lfllpUrlbeS If the addltlve llSelf IS flO( shown tO be CarClnOgHIC (~co/f v FDA

/,?8 F ?c! 322 16fh CI, <094 I % Oscusslon In Iexf

bALIIOII levels ~re InOI ,ecu(eo 10 De ~utylsheo for commenl Detore the] dre esfa~llshec

‘Coal fdr halt dy?s irc exempt fronl [he ~oul[erallon ana color acldlhve provisions found In sections 60 ~ & 706 of the FDCA (Z; U S C 361 376) Prov(ded the label bears a cauhon stafemen( & Patch lest Insfructlons to de[ermlne If the DrOdu Cf causes

\klfT Irrltallon I Fec I+q 43 I 101 ‘ 978 I

continued on next page

I
90 I d-l II III I I II
I

L--

Table 3-4.—FDA: Carcinogens Associated With Foods and Cosmetics—Continued

Substance When Identified Type of evidence

— —

Petition NPRM Final Type of action/comments

p-Cresidine 4-29-80 — — — — Hypothesized Impurity m FD&C Red

No 40

Dapsone (4,4’-Diaminodiphenyl- 3-25-80 — — — Hypothesized Impurity m FD&C

sulfone)

—

Yellow Nos. 5 & 6; not found

D&C Orange no 17 1-20-83 Animal, 2 species–mice, 4-16-69 — 4-1-83 Provisional Iisting expired for use m

rats ingested drugs and cosmetics

— — — — 8-7-86 Permanently listed for use m

externally applied drugs and

cosmetics

10-6-86 Response to objections

2-19-87 Clarification to preamble

2-4-83 Terminated provisional listlng for

ingested uses

8-6-86 Terminated provisional listing for D&C

Red No, 37

8-7-86 Permanently listed D&C Red No 19

for use in externally applied drugs

and cosmetics

10-6-86 Response to objections

2-19-87 Clarification to preamble

12-5436 Permanently listed for use in ingested

—

—

D&C Red Nos. 19 & 37 8-12-82

—

—

—

—

D&C Red Nos. 8 & 9 8-26-82

— —

— —

Animal, 2 species–rats, 4-14-69

mice

—

—

—

—

— — —

— —

— —

Animal, 1 species–rats 5-17-65

—

—

—

2,4-Diaminoanisole & 10-18-77, NCI study Animal, 2 species–rats, 10-19-77 (EDF);

2,4-Diaminoanisole sulfate–as

1-6-78

sent to FDA; 9-7-78, mice 12-14-77 (GAO

Ingredients in coal tar hair risk assessment recommendation)

dyes

2,4- Diaminotoluene 9-20-79; 6-30-83, risk – —

assessment

Dibutyltin diacetate–as 10-18-79; 5-23-83, risk Animal, 1 species–mice –

—

—

10-16-79

1-

8-

drug and cosmetic lip products in

limited amounts and in externally

applied drugs and cosmetics

Product warning statements required

in absence of statutory authority to

ban(2); 9-18-80, stayed by

consent order, U.S. Dist. Ct. for

the Southern Dist. of Georgia (Civil

Action No. CV 480-71) and

remanded to FDA for

reconsideration & further

rulemaking

5-80 Denied use of adhesive in which this

impurity formed

9-83, 4-2-84, Rule for safe use of non-carcinogenic

contaminant of assessment supplement to final food packaging additive that may

2.2-oxamidobis(ethyl 3-(3,5-di- rule contain dibutyltin diacetate. a The

tert-butyl-4-hydroxyphenyl) supplement discloses the identity

propionate) of the carcinogenic constituent

which previously was withheld as

trade secret

— — — — 12-4-85 Request for hearing was denied

D1-(2-ethylhexyl) adipate 11-12-80, 7-21-81, risk Animal, 2 species–rats, – — — Under study –indirect mechanism of

assessment mice action suspected

a

alh~ rule, fOr safe “Se are ~aSe~ on ~ , ~~q ~Our, @clS,On ~ha, ~,lOWed Safe ~xpoSure [eve[s 10 be ~S[abllShed for “Oncarclnogenlc addltlveS that con[aln CarclnOgenlc ,mpur,[les If [he addl[lve Itself IS nOt shown tO be carclnOgenlc (5COI( v ~~~

728 F 2d 322 (6th Clr 1984) J See discussion In text

ccoal far hair dyes are ~xempt from fhe ad”lteratlon and color addlflve provisions found In SectlOns 601 & 706 of the FOCA ( 21 U S C 361 376) prowded the label bears a C.au!lon statement & Patch tes( Insrructlons to de!ermme If ‘he product causes

skm Irnlatlon (Fed fteg 43 1101 1978)

continued on next page
Table 3-4.—FDA: Carcinogens Associated With Foods and Cosmetics—Continued

Substance When Identified —

Type of evidence Petition NPRM Final Type of action/comments

D1-(2-ethylhexyl) phthalate 11-12-80, 7-21-81, risk

assessment

8-21-79; 11-19-81, risk

assessment

Animal, 2 species–rats,

mice

Animal, 1 species–rats

— — — Under study, indirect mechanism of

action suspected

1,4-Dioxane–as impurity m 10

food contact additives & 1

saniatizing solution used on

food contact surfacesd

3-19-82, 4-22-83, – 9-28-83, 9-10-85,

6-14-84, 2-3-81, 8-13-86, 9-5-86,

4-20-84, 2-25-85, 9-19-86, 9-24-86,

12-28-79, 6-3-83, 9-24-86, 9-24-86,

9-8-83, 9-3-82, 12-31-86, 1-6-87,

3-5-86 1-7-87

Rules for safe use of food-contact

additives that contain 1,4-Dioxane

1,3-Dlphenyltrlazene

—in FD&C Yellow No 5 12-20-83, risk

assessment

Animal, 1 species–mice 3-27-65 — 9-4-85 FD&C Yellow No.5 permanently listed

for use m cosmetics and externally

applied drugs; contains

1,3-diphenyltriazene impuritya

Adopted uniform specifications

including specifications on

impurties, for all uses of FD&C

Yellow No. 5

Permanently listed Yellow No. 6;

contains 1,3-diphenyltriazene

impuriy a

Banned as food additive

—

11-20-68

— 9-4-85

—in FD&C Yellow No 6 — — 11-19-86

Dulcin (sucrol), (4-ethoxyphenylurea)no date

11-29-82, risk

assessment

Chrome toxicity data in

rats

1-19-50

8-19-83

— —

Epichlorohydrin-contained in

polyamide-epichlorohydrin

water-soluble thermosetting

resins (retention aid in paper

coating)

Amended regulations to remove upper

viscosity Iimit of the retention

aid–(used m paper coating as

indirect food additive); contains

epichlorohydrin impuritya

Clarification of final rule

Denied request for hearing

Animal drug, hormone naturally

occurring in animals

Rules for safe use of several food

contact additives that may contain

ethylene oxide impuritya

—

4-9-82 (Sandox Colors &

Chemicals)

—

4-24-84

12-4-85

4-9-84

—

11-14-79, 5-23-83, risk

assessment

1-5-82; 4-7-86, risk

assessment

—

—

—

— —

— —

17-b-Estradiol — —

Ethylene oxide–as Impurity m 9

food contact additivese

6-14-84, 2-3-81, —

4-20-84, 2-25-85,

12-28-79, 6-3-83,

9-8-83, 9-3-82,

3-5-86

8-13-85, 9-5-86,

9-19-86, 9-24-86:

9-24-86, 9-24-86,

9-24-86, 12-31-86,

1-6-87, 1-7-87

11-30-73

—

Ethylene thiourea (Impurity in 4-24-73

mercaptomidazoline)

No date ‘‘Known carcinogen’ — Banned mercaptolmldazohne and

2-mercaptiomidazoline m food

contact articles due to possible

Impurity

Flectol H (1.2-dihydro-2.2,4 -tri- Banned m food contact articles

methylquinoline, polymerized)

Hydrazine

No date

6-12-79, (cities IARC),

6-8-82, risk

assessment

5-2-85

4-7-67

—

Animal. 1 species

Animal, 2 species–mice,

rats

—

—

—

6-12-79 To prohibit food additive use,

permitted as a boiler water additive

with limitation of zero in steam

contacting food

Not permitted as a food ingredient;

petition requests food addiative

regulation

Lactitol — 5-19-83 —

continued on next page
Table 3-4.—FDA: Carcinogens Associated With Foods and Cosmetics—Continued

Substance When identified Type of evidence Petition NPRM Final Type of action/comments

Lactose 5-2-85

.

— — Natural component of food including

milk, FASEB report (9-86) states

Lead acetate 3-6-79, found to be Animal, 2 species–rats, 6-29-73 (Comm of

absorbed by skin. mice (by ingestion) Progressive Hair Dye

5-6-80, 5-23-80, risk Industry) requesting

assessment permanent listingf

12-10-63

4.4’-Methylenebis No date Animal, 1 species – —

(2-Chloroaniline)

Methylene chloride 1-20-83, 4-23-85, risk Animal, 1 species–mice – 12-18-85

assessment (suggestive m rats)

4,4’ -Methylene dianiline 4-7-83, 5-16-83, risk – —

assessment

b-Naphthylamine

—in FD&C Yellow Nos. 3 & 4 No date No carcinogenic evidence (Dye Stuffs & Chemicals) –

cited

–in FD&C Yellow Nos. 3 & 4 Cites 1974 IARC report Human, animal, 4 – —

species—mouse,

hamster, dog, monkey

—in Red Nos. 10, 11, Cites 1974 IARC report Human, animal 8-6-73 (for permanent 9-23-76

12, & 13 Iisting), withdrawn

10-21-77

—in Orange-B

Nitrilo triacetic acid

N-Nitrosodimethylamine

—as contaminant m malt

beverages

1-19-78, identified as Human, animal —

contaminant of

Orange-B

10-18-79 — —

10-3-78

—

—

that lactose IS not significantly

tumorigenic in humans, believes it

IS necessary to repeat animal study

0-31-80, 3-6-81, Permanently listed for use as color

response to objections additive in hair dyes

& removal of stay

2-2-69 Banned in food contact articles

Proposed to ban in cosmetics but not

—

10-12-60

in decaffeinated coffee because

risk was determined negligible

10-12-60

12-13-77

Denied petition of Dye Stuffs &

Chemicals to restore color additives

to provisional list with 25 ppm

tolerance in food, possible impurity

m these color additives

Provisional listing of these color

additives terminated because bnaphthylamine is possible impurity

Prohibited these color additives from

use in drugs & cosmetics because

b-naphthylamine is a possible

Impurity; terminated provisional

listing

— To revoke Iisting of Orange-B for use

m food; not certified for use m

food since 10-78

— —

1956 Animal, more than 2 – — 10-25-79, action level Action level established at lowest

species–rats, mice, announced in press level at which presence can be

others release b

: notice of confirmed in malt beverages

comphance guide

published 6-10-80

- —

alhe rules for safe use are based On a 1984 court Cteclslon that allowed safe exposure levels to be estabhshed for non carcinogenic addttwes that Conlaln carcinogenic lmpurltles If the acfdltlve Itself IS not shown to be carcmogemc (Scolf v FDA

728 F 2d 322 Irjth Clr 1984) ) See dlsCu5S10n in Iexf

bActlon levels are not required 10 be pubhshed for comment before the), are eslabhshed

dFood ~ontact addl~lves ~hlch Contain 1 4. Dloxane for ~hlch safe ~~e rules were issued ethylene Oxlrje adcjuct of 2479 feframethyl.5. decyn-4 7.dlol polyoxyefhylafed (5 moles) tallow amine and alpha alky(.omega.hydroxy Pofy (oxyelhylenel ethoxy~ated

ocladecylamlne reacted wdh octadecanolc acid alpha sulfo omega I dodecyloxy)poly (oxyefhylene) ammomum salt Impact modlfled Nylon fvl XD-6 sulfosucc!nlc dc!d 4ester wlfh polyethylene glycol nonylphenyl ether dlsodlum salt @L-alkyl(CIO-C 14)

omega- hydroxypoly (oxyethylene) poly(oxypropylene) and J@M alkyl( C 12 C 18)-orne9a hydroxypolyl oxyethylene) poly(oxyProPylene) polyoxyethylene cetyl alcohols Jnd Polyoxyethylene oleYl ether a/P~a-( P-nwlPhw )-~fllega-hydroxy polyloxyelhylene )

and dlethyleneglycol dlbenzoale Sanmzlng solullon used on food contact surfaces alpha-alkyl (C 11 Cl 5) omega hydroxypoly(oxy fheylene) and a/phd (p nonylphenyl) omega hydroxypoly(oxy ethylene)

eFood ~ontac[ addltlves Which may contain ethylene oxide for Which Safe “se rules were issued efh~xylaled oc[adecylam,ne reacted w,fh ocfadecanolc acid ,;/p/ra sulfo omega (dodecyloxy)poly (oxyefhylene ) ammonium salt Impact modlfled Nylon MXD-6

sultosucclnlc acid d-ester wdh polyethylene glycol nonylphenyl ether dlsodlum salf alphd alkyl(CIO-Cl 4)-omega. hydroxypoly (oxyethylene) PolYloxYPfoPYlene) and a/Pha alWCl ?-C 18)-ome9a hydroxy-Poly(oxYethy lenel PolYloxYProPYlene) Polyoxyelhy

Iene cetyl alcohols and polyoxyethylene oleyl ether d/phd-(p nonylphenyl) ornegdhydroxypoly loxyethylene) and dlethyleneglycol dlbenzoate

!The Petltlon was flied ,n response f. j 3,.73 no,lce (Fed ~eg 382996 1973)1 hat metalll~ salfs or vegetable colorants could no Ionger be markefed unless a pe[ltlon was filed by 7-30 73 In the NPRM MallufaCfurerS Were advised fhat they Were

not ellglble for coal far hair dye exemptions & dafa was requested to make flndl defermlnallon The closlng date was posfponed several times pending study Completions

continued on next page

I
Table 3.4.—FDA: Carcinogens Associated With Foods and Cosmetics—Continued

Substance – When indentified Type of evidence Petition NPRM Final Type of action/comments

—as contaminant m 5-chloro2-methyl-4 isothiazolin-3 -one

& 2-methyl-4-isothiazolin-3-one

5-Nitro-o-toluidine

2-Nitro-p-phenylenediamine

2-Nitropropane

N-Nitrosamines–as contaminants

in rubber baby bottle nipples

011 of Calamus

PCB’S (Arochlor)

P-4,000 (1-n-propoxy-2-amino-4-

nitrobenzene)

o-Phenylphenol

Polynuclear Aromatic

Hydrocarbons (PAH)

—in carbon black

—in graphite

Radioactive Contamination of

Food (accidental)

Saccharin

Safrole & Isosafrole

— . —

3-4-80

11-27-79

4-25-77 NIOSH Bulletin,

4-7-86, risk

assessment

1981, found as a

problem m rubber

baby bottle nipples

No date

9-23-80

No date

5-31-84

ACS Monograph #173

—

—

—

6-16-78

— 1-19-80, 2-22-80 to –

establish rule for safe

use

— — —

— —

Animal, 2 species–rats, – 12-1-78

rabbits

— — —

Animal, 1 species – —

— — 3-18-72 (& others)

Chrome toxicity data m – —

rats

— — —

Certrain PAHs are known 7-24-73 —

carcinogens

— 8-6-73 —

Based on guidance – 12-15-78 (proposed

issued by Federal ‘‘Protective Action

Radiation Council, Guidelines” for State

7-64, 5-65 and local agencies)

Animal, 1 species–rats – 4-15-77

Long term studies – —

2-1-85

—

—

—

12-27-83, action level

announced; revised

6-26-84

5-9-68

7-6-73 (& others)

1-19-50

—

9-23-76

11-29-77

10-22-82, prop

recommendations

withdrawn, issued

notice of recommendations (not codified)

Withdrawn

12-3-60

Rule established for safe use of

additive containing DMNA impurity

in adhesives and paper coating

which contact fooda

Hypothesized impurity in several color

additives; not found

Coal tar hair dye ingredient

To prohibit m food packaging

adhesives

Action level established at lowest

avoidable level (10 ppb m any

specific N-nitrosamine)

Banned use of calamus and its

derivatives m food

Tolerances estalished to

exposure

Banned as food additive

—

limit

Petition denied and provisional listing

terminated for use of carbon black

as color additive because PAH

possible impurity

Provisional listing terminated for use

of graphite in externally applied

cosmetics because contains PAH

Impurities

Recommended protective action at

0.5 rem whole body, 1.5 rem

thyroid; emergency protective

action (when there is high dietary

& social cost or impact) at 5 rem

whole body, 15 rem thyroid

Proposal to revoke as ingredient in

food was withdrawn because of

congressional action

Banned addition of safrole, oil of

sassafras and related substances

to foods; some GRAS substances

may contain miniscule amounts of

safrole. Cosmetics: low priority for

further evaluation because low

potency carcinogen with limited

exposure

continued on next page
Table 3-4.—FDA: Carcinogens Associated With Foods and Cosmetics—Continued

.———

Substance When identifed

2,3,7,8-Tetrachlorodienzo-p- 1026-78 risk

dioxin (TCDD) assessment

Tetrachloroethylene 5-13-80

Thiourea 6-16-78

Type of evidence Petition NPRM Final Type of a acation/comments

Unavoidable contaminant. advisory

issued to Great Lakes States on

TCDD in fish in 1981

—

Possible cosmetic ingredient, no

longer used in cosmetics to FDA’s

knowledge

Impurity in several color additives

found along with p-toluidine, but at

lower levels, p-toluidne

Specification also Iimits o-toluidine

— — —

Animal, 1 species–mice – — —

—

o-Toluidine 4-1-80 — — —

p-Toluidine

–as contaminant of D&C 2-24-81, 2-24-81, risk

Green No 6 assessment

Animal, 1 species–mice – 3-21-86

.

10-27-86 Adopted uniform specifications,

including specification on ptoluidine impurity, for all suture

uses of D&C Green No. 6

Permanently listed D&C Green No, 6

for use in externally applied drugs

& cosmetics; contains p-toluidine

impurity a

Listed D&C Green No. 6 for use in

contact lenses

Provided for additional uses of D&C

Green No. 6 for coloring

absorbable sutures

Adopt uniform specifications,

including specification on ptoluidine impurity, for all suture

uses of D&C Green No 6

Permanently listed D&C Green No, 5

for use in drugs and cosmetics,

contains p-toluidine impuritya

Permanently listed D&C Red Nos. 6 &

7 for use in drugs & cosmetics,

contains p-Toluidine impuritya

Permitted for use in food packaging

adhesives

Agency Information indicates coffee

decaffeination and cosmetic uses

discontinued

— — 11-20-68 4-2-82

— 1-14-83, 1-28-83 (3

petltlons)

— 2-14-85, 3-29-83

— 3-29-83

— 3-21-86

—

—

— — — 3-21-86 10-27-86

–as contaminant of D&C –

Green No. 5

— 11-20-68

— 8-6-73

— 6-4-82, 11-2-82, stay

removed

–as contaminant of D&C Red –

Nos. 6 & 7

— 12-28-82; 7-29-83, stay

removed

1, 1,2-Trichloroethane 11-20-79 Animal, 1 species–mice –

Animal, 1 species–mice 6-24-75 (HRG)

— —

1, 1,2-Trlchloroethylene 3-21-75 NCI report 9-27-77 —

aThe ~uIe~ 10( safe “se are ba@ on a 1984 Courl dc?clslon fhaf allowed safe ex~osure levels 10 be established for non [ arclnogenlc addlflves that [ onlwl r lrclnogenlc lfll Pur Itles If the Jddl{lve Itself IS nOt shown [0 he cdrc(n09enlC 5COI; . FDA

728 F 2d 322 (6th Clr 1984) ) See discussion In text

Ccoa( tar hair dyes are exempt from the ad Ljllerallon and ~olo, ~ddlt,ve ~rovl Clo(l~ fou “d ,n .je~IIOn S fjo 1 & 705 of the FDCA ( 21 (J S C 364 3715 I Orovlrjed the label bec~rs a C,l,jll[]n s[,i[emprlt & Ua[ch feSl 1,1 Sfru Cll OnS to C!3[(?rf11(rl~ If the OrOCULl C,3US!?S

skin Irrdallon I fed Reg 43 1101 1978 I

continued on next page
Substance When identified Type of evidence Petition NPRM Final Type of action/comments

Trimethylphosphate

Urethane

—impurity in

diethylpyrocarbonate

—in alcoholic beverages

Vinyl chloride (impurity in vinyl

chloride polymers)

Includes risk assessment

No date

—

1-4-73, identified in

alcoholic beverages

stored in vinyl chloride

polymer containers

1974

—

Cites 1979 IARC

Monographs; 5-27-82

(risk assessment)

Animal, 2 species–rats, 1-28-80 (Sunkyong – — Petition for use of trimethylphosphate

mice

Not regarded as safe,

evidence citedg

Human

Animal

Animals, 3 species–

2-11-72

—

5-17-73

4-2-74

9-3-75

2-3-86

Fibers) -

in manufacture of polyethylene

phthalate polymers; withdrawn

4-4-80; impurity in pesticide used

in animal feed

no — 8-2-72 Banned diethylpyrocarbonate because

urethane is possible impurity

11-24-86 CSPI is requesting recall of alcoholic

beverages adulterated with high

levels of urethane

— Withdrawn 9-3-75 Re: restriction from use of vinyl

chloride polymers in alcoholic

beverage containers

— 8-26-74 Prohibited use of vinyl chloride as

ingredient of drug & cosmetic

aerosol products, NDA required for

use in drugs

— Withdrawn 2-3-86 Re: restriction on use of vinyl

chloride polymers in contact with

food

— Pending Rule for safe use of vinyl chloride

mice, rats, hamsters potymers based on new technical

capability to reduce levels of vinyl

chloride monomer in vinyl chloride

polymer resin and on new interpretation of legal requirements

aThe ~ule~ fOr safe “se are based on a 1984 courf declslon t~f allowed safe exposure levels to be estabhshed for non-carclnogemc addltwes that COntaln Carclnogemc Irnpurltles If the addmve Itself IS nOt shown to be Carcmogenlc (SCOff V ~~~

728 F 2d 322 (6th Clr 1984) ) See discussion m texl

gNo carcinogenic evidence IS cited by the FDA for this action However It IS hsled as a carcmogemc substance In the NTP ArmJa/ Report
97

was extended to substances covered by the Delaney clause, under a de minimis interpretation

of that clause. In 1985, FDA proposed to allow

the continued use of methylene chloride as a direct food additive based on the results of a risk

assessment. In 1986, some carcinogenic color additives were permanently listed based on the results of risk assessments (see below).

Regulatory Actions on Carcinogens

in Foods and Cosmetics

FDA actions concerning carcinogens in foods

and cosmetics can be grouped based on the type

of material and the kind of FDA action. The types

of materials are direct food additives, indirect

food additives (generally from packaging materials and food-processing equipment), color additives (both for ingestion and for external use

only), contaminants or potential contaminants of

food or color additives, unavoidable environmental contaminants in foods, and cosmetic ingredients. FDA actions may include banning the

substance (or terminating a provisional listing),

setting a rule for safe use of an additive, requiring warning labels, and setting tolerances and action levels.

Prior to 1958, the FDA had prohibited the food

additive use of two carcinogens: Dulcin (4-ethoxyphenylurea) and P-4000 (1-n-propoxy-2-amino4-nitrobenzene), both in 1950 (see table 3-4). Since

then, FDA has banned four direct food additives:

safrole (1960); oil of calamus (1968); diethylpyrocarbonate (DEPC) (1972), which forms the

carcinogen urethane); b and cinnamyl anthranilate

(1985). FDA has also proposed to prohibit the use

of hydrazine, trichloroethylene, and Saccharin as

food additives. The proposal for Saccharin was

issued in 1977 but was not made final because of

congressional action mandating that Saccharin remain on the market. For hydrazine and trichloroethylene, no final action has been taken.

FDA is also proposing a rule to allow the continued use of methylene chloride to decaffeinate

coffee (in contrast to banning its use in cosmetics).

This use for decaffeination is being justified on

6Urethane has been in the news lately because it is found as a byproduct of fermentation in several types of wines and distilled spirits.

FDA has been petitioned to take action on urethane levels.

the grounds that an assessment reveals that the

risk from this use is de minimis.7

Indirect food additives are generally packaging materials in contact with food and processing equipment. FDA has banned outright two indirect food additives: flectol-H (1967) and MBOCA

(1968). In the mid-1970s, FDA had also banned

certain uses of bottles made from acrylonitrile

copolymers and polyvinyl chloride because of

concern that residual acrylonitrile and vinyl chloride might leach into the liquids contained in the

bottles. In the 1980s, FDA issued a rule to allow

acrylonitrile copolymer bottles and proposed to

allow polyvinyl chloride bottles. FDA’s argument

is that new manufacturing technology can assure

that leaching of the residual chemicals from these

bottles will be minimal and that FDA has the authority to establish specifications for carcinogenic

impurities in regulations for the safe use of additives. FDA has also issued a safe use rule for Epichlorohydrin (1983), dibutyltin diacetate (1983),

1,4-dioxane (1985), dimethylnitrosamine (1985),

and ethylene oxide (1986), which are carcinogenic

impurities of certain packaging materials. FDA

has proposed, but not taken final action on, other

indirect food additives in packaging materials:

2-nitropropane and chloroform.

Under the Color Additives Amendment of

1960, FDA established a provisional listing of

color additives then in use with the aim of reviewing their suitability for permanent listing for use

in foods, drugs, and cosmetics. The original

amendments gave industry 2

1/2 years (until the

end of 1963) to demonstrate the safety of provisionally listed color additives. However, FDA has

extended this deadline a number of times since

then. Although the provisional color list was

established shortly after enactment of the Color

7Two other well-publicized actions involved some concern for carcinogenicity, although FDA’s final decisions were ultimately based

on other grounds. In 1969 FDA removed cyclamates from its lists

of GRAS substances. While initially there were concerns about a

positive animal study, after review FDA concluded that cyclamates

were not carcinogenic. But the listing termination was continued

because it was not shown to be safe. In 1976, FDA removed FD&C

Red No. 2 from its provision] list of color additives because FDA

was not convinced of the safety of this additive. This decision was

based partly on an inconclusive study on carcinogenicity. Furthermore, no studies were under way to provide the data necessary to

establish safety. Because these chemicals were additives, the manufacturer has the burden of providing this evidence.
98

Additives Amendment in 1960, the process of obtaining the necessary toxicity data and making

regulatory decisions has lasted until now.

Today, 25 years later, there are only a few substances left on this provisional list. For a given

color additive, FDA regulatory actions described

in table 3-4 include terminating the provisional

listing of a color or placing it on the “permanent”

list. The provisional list originally included over

200 color additives. As of 1985, from the original list, 126 have been permanently listed, 63 have

been removed from the market, and 10 have remained on the “provisional” list (210).

FDA has terminated the provisional listing of

several color additives, effectively banning them,

because they were carcinogenic or potentially contaminated with a carcinogen. These include Ext.

D&C Yellow Nos. 9 and 10; D&C Red Nos. 10,

11, 12, and 13; orange-B (which may contain betanaphthylamine); Ext. D&C Yellow No. 1 (which

may contain benzidine and 4-aminobiphenyl), and

carbon black and graphite (containing polynuclear

aromatic hydrocarbons). FDA permanently listed

lead acetate as a color additive for use in hair dyes

in 1980, arguing that the lead exposure was small

compared to background exposure and that the

estimated risk was insignificant.

Since 1982, following its “impurities policy” (described above), FDA has permanently listed several colors even though they contain known carcinogens. These include D&C Green Nos. 5 and

6, and D&C Red Nos. 6 and 7 (all containing ptoluidine), FD&C Yellow No. 5 (containing 4-

aminoazobenzene, 4-aminobiphenyl, aniline, azobenzene, benzidine, and 1,3-diphenyltriazene),

FD&C Yellow No. 6 (containing 4-aminoazobenzene, 4-aminobiphenyl, aniline, azobenzene, and

1,3-diphenyltriazene), and CI Vat Orange No. 1

(containing CI Vat Yellow No. 4 as a contaminant).

In 1986, FDA applied a de minimis policy to

colors that themselves are carcinogenic in animal

studies. D&C Red Nos. 8, 9, and 19, and D&C

Orange No. 17 were identified by FDA as carcinogenic in 1982 and 1983. D&C Red No. 9, in fact,

tested positive in a National Toxicology Program

(NTP) bioassay. In theory, based on the traditional interpretation of FDCA, these carcinogenic

color additives should be candidates for banning

from drugs and cosmetics. In August and December 1986, FDA permanently listed these colors,

arguing that the estimated risk was low. In a February 1987 Federal Register notice, FDA went on

to argue that because the estimated risk in humans

was low, the color additives in question were, for

purposes of the Delaney clause, not animal carcinogens either, notwithstanding the bioassay results. In the August notices, FDA had stated that

each of these colors (D&C Orange No. 17 and

D&C Red No. 19) “induces” cancer in animals.

In the new notice it explained:

This statement reflected FDA’s policy, as a

matter of scientific analysis . . . that any chemical shown to induce cancer even in only one

strain, gender, and species, at one dose in one

experiment, is an animal carcinogen. This statement did not represent a conclusion that this substance induces cancer in animals within the

meaning of [the Delaney clause]. . . .

. . . a conclusion for purposes of the Delaney

clause that a substance at a given level poses a

de minimis risk to humans implicitly includes the

conclusion that a de minimis level of risk at a

comparable level of exposure is presented to animals. Accordingly, D&C Orange No. 17 [and

D&C Red No. 19] can not be said to induce cancer in animals, as well as in man, within the

meaning of the Delaney clause. When a substance causes only a de minimis level of risk in

animals, it cannot be said to induce cancer in animals within the meaning of the Delaney clause

[239,240].

FDA has also acted on certain other ingredients

of cosmetics. It has banned vinyl chloride in aerosol products, prohibited chloroform in cosmetics, and proposed to ban methylene chloride

from cosmetics. FDA also attempted in 1979 to

require a label on coal tar dyes (which contain

2,4-diaminoanisole and its sulfate) warning of animal evidence for carcinogenicity. In 1980, a Georgia court, in a consent decree, remanded this regulation back to FDA for further consideration,

including development of a risk assessment. No

further action has occurred.

For potentially carcinogenic unavoidable environmental contaminants, FDA has set regulatory

tolerance levels for fish contaminated with PCBS.

FDA has also set the more informal action levels
99

for aflatoxins, dimethylnitrosamines (in malt

beverages), and N-nitrosamines (in baby bottle

nipples).

The direct food additives that FDA has banned

are generally carcinogenic in a single species. For

the color additives that FDA has banned, the carcinogenic substances at issue were beta-naphthylamine, benzidine, 4-aminobiphenyl, and polyaromatic hydrocarbons—all of which are known

human carcinogens and carcinogenic in several

animal species. For most other color additives and

indirect additives for which safe use rules were

issued, the original determination of potential carcinogenicity from impurities or substance migration was usually based on animal data, often in

one species.

Table 3-4 also indicates a number of substances

that FDA has identified as carcinogenic, but for

which no final regulations have been issued. In

FDA’s view, most of these regulations were not

needed because the hypothesized impurity was

never actually found or the risk was determined

to be insignificant. FDA still might take action on

a case-by-case basis if a problem was discovered

(182).

Regulation of Animal Drug Residues

Prior to 1962, animal drug residues in food were

subject to the Delaney clause, but in 1962 Congress enacted the “DES (Diethylstilbestrol)

Proviso,” which permits the use of carcinogenic

drugs in animals, providing that their residues

could not be detected in edible portions of tissue

or foods derived from living animals according

to methods approved by FDA. (See chapter 2 for

a discussion of the sensitivity of method for detecting such substances. )

FDA identified (in its response to OTA) 16 carcinogens that are or were administered as drugs

to animals, or are potential drug contaminants,

and that might leave residues in animal tissues to

which people may be exposed. FDA banned the

use of DES in animal drugs, denied approval of

one substance (which was however overturned in

court) (Gentian violet), and has proposed to withdraw seven other substances. FDA has required

residue studies on six substances, including four

that it has proposed to withdraw. Three of those

four were instead regulated under FDA’s policy

for endogenous or naturally occurring hormones

under which a certain amount of increase over

the naturally occurring levels is permitted.8 For

two substances, residue studies are all that FDA

has required. In the case of Reserpine, the sponsor withdrew the application for approval, while

for three other animal drugs, no actions are expected (see table 3-5). For one substance, aniline

hydrochloride, which is a contaminant of an animal drug, FDA required that it’s levels be reduced.

The only animal drug successfully banned is

DES, on which there is human evidence from human uses of this drug. The lack of action on potentially carcinogenic animal drugs has also been

criticized by the House Committee on Government Operations. In particular, the committee

indicated that even though FDA has determined

several animal drugs were carcinogenic (dimetridazole, ipronidazole, and carbadox), FDA has not

removed these drugs from the market nor has it

required that adequate residue monitoring methods be developed. In addition, while FDA had

never given premarket approval to Gentian violet and its seizure orders had been supported in

a number of courts, FDA has temporarily stopped

seizing products containing Gentian violet because

one lay jury determined this use to be “generally

regarded as safe.” Later animal tests revealed Gentian violet to be an animal carcinogen. The Committee criticized FDA for failing to take some action based on this evidence (211).

Regulation of Carcinogenic

Human Drugs

Human drugs are subject to premarketing approval based on risk-benefit criteria for the intended condition of use (233). When a drug has

a significant effect on an incapacitating or fatal

8The hormone policy was announced in guidelines for toxicological testing published in conjunction with FDA’s proposed sensitivity of method procedures (mentioned above). Under the hormone

policy, FDA distinguishes between endogenous and synthetic hormones. Endogenous hormones are regulated based on the increase

over endogenous levels of the hormone found in the residue studies.

For synthetic hormones, a study is required to determine the hormone no-effect level. If they cause tumors only in the endocrine target

organs, the safety standard is based on the no-effect level. Otherwise the standard is based on the carcinogenicity study (102).
Table 3-5.—Potentially

—

When identified

Drug (type of evidence)

Carcinogenic

Petition

Animal Drugs Considered for Regulation by FDAa

Proposal to withdraw Final Court action/challenae

Aniline hydrochloride — — —

Carbadox (& metabolites) 1978 (animal–rats, mice) 5-9-86 —

DESb1964 (animal–mice), no date None 3-11-72 (premixes)

(human)

—

—

Dimetridazole 1971

3.5-Dinitrobenzamide 1970

Estradiol benzoate 1974

— 1-12-76 (hearing granted

11 -26-76)

— 6-21-72 (premixes & implants)

— 3-27-74 (to revoke method of

analysis)

(animal–rats) 5-9-86 12-17-86

Level of contaminant reduced

Required residue & metabolism

studie s

8-4-72, (premixes)

9-21-79

4-27-73 (Implants)

—

—

(animal–rodent) c — — Level of human exposure from

(IARC, literature reviews re None

sex hormones)

Estradiol monopalmitate 1974 (IARC, literature reviews re None

sex hormones)

Furazolidone 1964 (animal–rats, mice None

tumorigenic evidence), 1974

(carcinogenic evidence)

—

-5-79 (9-22-72, requested more

residue data)

-5-79 (requested more residue

data 9-22-72)

-4-71, 5-13-76, 9-4-84

use m animals to determine

further testing for hazard

Residue studies provided

No residue studies provided

—

—

Reversed & reinstated, Hess & Clark

V. FDA, 161 U.S. App. D.C 395,

495 F.2d 975 (DC Cir 1974)

DES IS no longer permitted for use m

animal drugs, upheld Rhorre

Poulenc, Inc , Hess & Clark

Division v FDA, 636 F.2d 750

(DC. Cir, 1980)

—

Chemetron Corp. v U S DHEW, 95

F.2d 995, 997 (0 C. Cw. 1974)

—

—

Regulated under FDA hormone policy

—

Administrative Law Judge initial

decision recommends withdrawal

of NADAs, 11-12-86

%ther potentially carcinogenic animal drugs were mentioned In hearings on the “Regulation of Animal Drugs by the FDA” before the House Committee on Government Operations which were not mentioned

in the information provided by the agency In response to the OTA request These Include Al bendazole which was found carcinogenic in rats and mice by the CVM Cancer Assessment Committee in a July

1984 meeting. In 1979 it had been regarded as a suspect carcinogen and was not approved except for emergency and investigational use It was ordered off the market in a letter dated Nov 8, 1984 (Hearings,

p. 424). A proposal to withdraw dibutyltln dilaurate was issued Aug. 29, 1978 but, according to an agency memo, products that contain it are still marketed under other NDAs. Dibutyltin dilaurate is a suspect

carcinogen because it is related to dibutyltin diacetate which is carcinogenic according to NTP results. (Hearings, p. 187; FDA memorandum “Re-evaluation of the Status of Certain Marketed Drugs.”) The

memo also mentions Ronnel which IS potentially contaminated with dioxin which IS carcinogenic in rats. According to the memo however, the agency did not have enough evidence to take regulatory action

and recommended requesting more data on the level of dioxin contamination in Ronnel (Hearings, pp. 188-189).

It was also noticed that iron dextran complex and several estrogens are regulated according to information in the Annua/ Report on Carcinogens but do not appear on the list provided by the FDA. It also

appears from the hearing documents that several substances may have been regulated through informal procedures, such as Albendezole which was regulated by correspondence between the agency and

the sponsor so the Iistlng may not be complete

bln 1962 congress enacted the IDES Exception t. the Delaney Clause,, permitting the use of carcinogenic drugs In animals providing that they could not be detected in edible portions Of tiSSUe Or foods

derived from Iiwng animals according to methods determined by the FDA In 1962, regulations were promulgated permitting the use of DES and establishing detection methods. In the early 1970s however,

the USDA found residues at levels below the sensitivity of the prescribed method

CThe drug ,s regulated as a Carcinogen under the ‘DEs Exception., (see footnote b) Information about the Identification of the drug as a carcinogen and the type of ewdence relied on Was not provided

continued on next page
Table 3-5.– Potentially

When indentified

Drug (type of evidence)

Gentian violet 1985 (preliminary animal

evidence-mice) c d

Ipronidazole e

1978 (animal)

Melengestrol acetate Animal c

Nitrofurazone 1964 (animal–rats mice

Carcinogenic

—

Animal Drugs Considered for Regulation

Petition Proposal to withdraw

Denied approval 3-30:

79

5-9-86 Proposal to withdraw

recommended by CVM in 1984

— —

None 3-31.71 8-17-76 9.4-84

tumongenic evidence), 1974

(carcinogenic evidence)

Progesterone c — 1.5-79

Reserpine — —

Testosterone propionate c — 1-5-79

Zeranol Animal’ — —

—

—

—

by FDAa—Continued

Final Court action/challenge

.

Overturned approved for use as mold

inhibitor in poultry feed Marsha//

Minerals v FDA 661 F.2d 409

(5th Cir. 1981)

—

Same as furazolidone

Residue studies provided Regulated under FDA’s hormone

policy

5-16-84 —

Residue studies provided Regulated under FDA’s hormone

policy

Required residue studies and –

chronic bioassay

ao~h~~ ~O~en~ial 1 ~ ~arcl “Ogenic ~nlmal drugs were ~entloned in hea~in~~ on the ‘(R~~ulatl~n of Animal Drugs by-the FDA” before the House Committee on Government Operations wh!ch Were not–mentioned

I n the Information provided by the agency In response to the OTA request These include Al bendazole which was found carcinogenic In rats and mice by the CVM Cancer Assessment Committee In a July

1984 meeting In 1979 It had been regarded as a suspect carcinogen and was not approved except for emergency and Invest lgatlonal use It was ordered off the market In a letter dated Nov. 8, 1964 (Hearings,

p 424) A proposal towithdrawdlbutyltin dilaurate was Issued Aug 29, 1978 but, according to an agency memo, products that contain it are still marketed under other NDAs. Dibutyltin dilaurate IS a suspect

carcinogen because It is related to dibutyltin diacetate which IS carcinogenic according to NTP results. (Hearings, p 187, FDA memorandum “Re-evaluation of the Status of Certain Marketed Drugs.’”) The

memo also men tlons Ronnel wh!ch is potentially contaminated with dioxin which is carcinogenic in rats. According to the memo however, the agency did not have enough evidence to take regulatory action

and recommenced requesting more data on the level of dioxin contamination in Ronnel (Hear!ngs, pp. 188-189).

It was also noticed that iron dextran complex and several estrogens are regulated according to information in the Annual Report orI Carcinogens but do not appear on the list provided by the FDA. It also

appears from the hearina documents that several substances may have been regulated through informal procedures, such as Albendazole which was regulated by correspondence between the agency and

the sponsor so the listi~g may not be complete,

bln 1w2 congress enacted the I.DES Exception t. the Delaney clause, permitting the use of carcinogenic drugs in animals providing that tfley could not be detected in edible pOr’tiOnS Of tiSSUe or foods

derived from living animals according to methods determined by the FDA In 1962. regulations were promulgated permitting the use of DES and establishing detection methods In the early 1970s however.

the USDA found residues at levels below the sensitivity of the prescribed method

CThe drug ,s regulated as a carcinogen under the ,,DES Exception, (see footnote b), Information about the Identification of the drug as a carcinogen and the type Of evidence relied Ofl Was not provided

dGent, an “,olet ,~ included on the Ilst FDA provided t. OTA of compounds being considered for regulation because of concerns about CarClnOgeniCitY but no ewdence IS Cited for carclno!lenlcconcern The

FDA held that gentian violet IS not “Generally Recognized as Safe” (GRAS), however, a jury held that it IS GRAS as a mold Inhlbltor In poultry feed up to 8 ppm (Fed Reg. 47 ”32480) No earl!er cltatlons were

provided According to an agency memo submitted at hearings on “The Regulation of Animal Drugs by the FDA” before a subcommittee of the Committee on Government Operations of the House of Represen.

tatlves, July 24 and 25. 1985 (pp. 180-181) a preliminary review of a long-term feeding study Indicated that gentian violet IS carcinogenic in mice Previously, It was only known that the main component of

gentian violet, crystal violet, IS related to compounds that are known animal carcinogens and two compounds With evidence of human carcinOcJenlclW The FDA had denied approval for Its use Mar 301979

4419035 and denied a hearing on the matter The declslon was overturned on grounds that It was a disputed question as to whether gentian violet was a carcinogen Marshall Minerals v FDA 661 F 2d 410

(1 lth Clr 3-28-80)

elpron,da~ole was the su b,e.ct of a causal review , n 1980 and was recommended for withdrawal by the Center for Veterl nary Medicine I n 1983 (a causal revlf?W IS an agefl CY Procedure for revlewln9 SafetY and

effectiveness data based on problems IdentIfled In reports of adverse drug reactions and serves as the basis for requesting regulatory supplemental NADAs) Concern was ra!sed In a pet ItIon filed by the

Center for Science In the Publ!c Interest (CSPI) because Instead of Intt!atlng proceedings to withdraw the drug In December 1985 It was Ilsted among the ‘“highest prlorltles for causal review A dectslon

on the petlt!on IS pendl ng

fzeranol ,s a suspect Carcinogen based on a chron,c bioassay of zearalenone Which has a Similar structure It IS currently under review and chronic blo==ays of Zeranol are underway

SOURCES EPA response to OTA request and cited Federa/ F?egfster notices. hearings on the ‘Regulation of Animal Drugs by the FDA before the House Commtttee on Government Operations 99th Congress

July 24 25 1985 p 66 pet!tlon to Withdraw New Animal Drug Appltcallons submitted to the FDA by the center for $hence In the Publlc Interest
1 0 2

disease for which there is no safe therapy, it could

be regarded as adequately “safe” despite major,

even life-threatening, side effects, such as carcinogenicity (233). A drug manufacturer must

submit an Investigative New Drug (IND) Application to conduct preliminary investigation of the

safety and efficacy of the drug and a New Drug

Application (NDA) for marketing approval. The

NDA is to include reports of the investigation to

show the drug is adequately safe and effective,

a list of the drug’s composition, samples of the

drug, information that might be required for FDA

monitoring activity, and proposed labeling.

For approved drugs, the prescription drug labeling must include a precautionary section that

states the results of carcinogenicity studies. The

usual type of FDA regulatory action in the drug

review and approval process is to informally require the drug sponsor to modify the warning information in the physician labeling.

FDA has rarely used the more formal process

of publishing a notice in the Federal Register to

regulate drugs for carcinogenicity, as it has done

for certain generic drugs or drug classes. FDA removed or the sponsor recalled from the market

as active drug ingredients chloroform (1976),

methapyraline (1978), and Phenacetin (1984).

Precautionary labeling was instituted by this process for estrogenic drugs (1976, 1977), neuroleptic

drugs except Reserpine (1978, 1980), and Reserpine (1983) (see table 3-6). FDA relied on human

evidence for Phenacetin and estrogens, although

positive animal evidence later became available

for Phenacetin. FDA relied on animal evidence

to evaluate the carcinogenicity of the other drugs.

Questions have been raised about whether FDA

has always acted on positive carcinogenicity evidence in this way and whether FDA has always

required sufficient information to make appropriate judgments about the safety of potentially carcinogenic drugs. For example, the House Committee on Government Operations has criticized

FDA for approving Zomax as a nonsteroidal antiinflammatory drug even though animal studies

indicated a carcinogenic response, and clinical

studies did not clearly show that this drug was

superior to other available treatments. The committee also expressed concern that a number of

other drugs of this class had been approved without adequate evidence on safety (209). FDA officials, on the other hand, argue that Zomax was

superior to other treatments and that the animal

data did not reveal a “carcinogenic” response, but

rather an increase of a benign tumor type that they

did not consider to be “a very alarming finding. ”

This increase was to be noted on the drug labeling (69).

Table 3-6.—Human Drugs Regulated as Carcinogens by FDAa

Type of

Substance evidence NPRM Final Type of action

Chloroform . . . . . . . . . . . . . . . Animal 4-6-76 6-24-76 Removed from market

Methapyraline . . . . . . . . . . . . . Animal — 6-13-78 Voluntary recall

(order)

Phenacetin . . . . . . . . . . . . . . . Human 8-10-82 10-5-83 Removed from market

Animal — amended

— 2-23-84

Neuroleptic drugs . . . . . . . . . Animal— — 5-16-78; Cautionary labeling; data reviewed for four

rats, mice amended 8-18-78; drugs, but labeling required for all

revised 8-8-80 related drugs (except for reserpine)

a

This table only includes drugs removed from the market or formally regulated after marketing approval. Carcinogenic drugs which require warning label are discussed

in ch. 5,

SOURCE: FDA response to OTA request; cited Federal Register notices.
1 0 3

CPSC REGULATORY ACTIONS

Activated in 1973, the Consumer Product Safety

Commission (CPSC) is an independent regulatory

agency. Its authority to regulate carcinogens is

established by both CPSA and the Federal Hazardous Substances Act (FHSA). CPSA authorizes

the regulation of most consumer products that

pose “unreasonable risks” of injury or illness.

FHSA was initially enacted in 1960 as a labeling

statute intended to fill gaps in other statutes.

FHSA was later amended to permit more drastic

action to control hazards and expanded “to cover

hazardous substances in general use in the home,

and particularly to protect children from hazardous toys and products. ”

Under CPSA, when a product poses an “unreasonable risk” of injury or illness, CPSC may

promulgate a consumer product safety standard,

ban the product from commerce when a safety

standard would not be adequate to protect the

public, bring suit in Federal district court to seize

an “imminently hazardous” product or seek an

injunction against the distribution of the product,

or require certain remedial actions. In 1981

amendments to the act, Congress required CPSC

to convene a “Chronic Hazard Advisory Panel”

(CHAP) prior to regulating products that present

a risk of cancer, mutations, or adverse reproductive effects. Under FHSA, hazardous substances

are labeled and may even be banned, but more

formal rulemaking procedures are required than

under CPSA.

In the 16 years since its creation, CPSC has

evaluated and attempted to regulate or begun to

regulate 6 individual carcinogens (vinyl chloride,

1974; tris(2,3-dibromopropyl)phosphate (tris),

1977; benzene, 1978; formaldehyde, 1981; diethyl

hexyl phthalate (in process); nitrosamines, 1984)

and 2 classes of carcinogens—benzidine congener

dyes (begun in 1978, not pursued after 1982); and

asbestos in various forms (1973, 1977) (353). (See

table 3-7 for a summary. )

In 1974, CPSC banned vinyl chloride (used as

a propellant in aerosols) as a hazardous substance

under the FHSA. The rule was overturned on procedural grounds, but by then the manufacture of

aerosols containing vinyl chloride as a propellant

had ceased. For this rule, CPSC relied on the risk

assessments conducted by other agencies (353).

In 1977, CPSC attempted to ban the use of tris

in children’s sleepwear. In this case, CPSC conducted its own risk assessment. The regulatory

action was overturned in court on procedural

grounds, but CPSC issued a statement of policy

that it was prepared to prove in court that tris

products were “banned hazardous products”

meriting judicial relief. CPSC brought several suits

in 1977 and 1978, and its strategy was upheld

(126). In 1978, CPSC proposed to ban benzene

as an intentional ingredient or a contaminant in

consumer products (except in gasoline and laboratory solvents), but did not finalize its proposed

rule because “by 1980, in response to the Commission’s action and other factors, the use of benzene in consumer products was virtually nonexistent . . . [thus] . . . The proposed ban was

withdrawn in 1980” (353). In 1978, as a result of

a petition, CPSC studied the carcinogenic effects

of benzidine congener dyes, but concluded by

1982 that their use had virtually ceased in consumer and commercial dye markets, and thus

decided no regulatory action was needed (353).

CPSC has regulated asbestos in several different products. In 1973, it banned general use garments containing asbestos (126). In 1977, it

banned the use of patching compounds and emberizing materials containing asbestos (the latter

was used in artificial fireplace logs), and in 1979,

it negotiated voluntary agreements with hairdryer

manufacturers to stop using asbestos shields in

hairdryers. The agency recently issued an enforcement policy which required labeling of household

products that contain intentionally added asbestos

that is likely to be released in use (230).
104

I I l l I I I I

0

0

I

I I I I

I

I I

I

I I l l I I l l
105

In 1981 CPSC issued a rule banning urea-formaldehyde foam insulation (UFFI). The Court of

Appeals for the Fifth Circuit struck down CPSC’s

ban. In particular, the court argued that because

of uncertainties in the risk assessment based on

an animal study, CPSC could not validly conclude

that UFFI presented an unreasonable risk (see further discussion in app. A). CPSC is currently engaged in a voluntary effort with the pressed wood

industry to develop national consensus standards

on formaldehyde emissions from their products

and has decided not to convene a CHAP at this

time (286).

At present, CPSC is studying diethylhexyl

phthalate (DEHP), a plasticizer in polyvinyl chloride products, and nitrosamines found in rubber

pacifiers, CPSC convened a Chronic Hazard Advisory Panel in the case of DEHP; the use of

DEHP in pacifiers has apparently ceased. CPSC

issued a statement indicating it would bring court

action under FHSA if nitrosamines in pacifiers exceed 60 ppb (353). CPSC is also working on a

voluntary standard to lower the level still further

(227).

Finally, CPSC is considering regulating several

other carcinogens: methylene chloride, perchloroethylene, and p-dichlorobenzene. In the

case of methylene chloride, CPSC is currently engaged in a proceeding to determine if it can be

called a hazardous substance under FHSA. No

final actions have been taken on any of these

chemicals.

In attempting to regulate carcinogens, CPSC

has for the most part relied on both human and

animal evidence, although for tris and formaldehyde, it relied on animal evidence only (see table

3-7).

EPA REGULATORY ACTIONS UNDER THE CLEAN AIR ACT

Some of the first major environmental statutes

enacted in the early 1970s were the Clean Air Act

Amendments of 1970. The statute provides an

elaborate Federal-State scheme for controlling

conventional pollutants, such as sulfur dioxide

and carbon monoxide. Because of the emphasis

on controlling conventional air pollutants, toxic

pollutants were almost ignored. But a provision

was added authorizing EPA to set emission standards for “hazardous” air pollutants, which provide “an ample margin of safety. ” The general

scheme is that a pollutant is first listed as hazardous based on pertinent scientific data. Then uniform national standards are to be established for

each source category of such pollutants within a

specified time.

However, Congress provided no explicit guidance for regulating carcinogens as compared with

other hazardous substances under this section.

This failure to address carcinogens explicitly has

led to considerable controversy in interpreting the

statute for application to carcinogens. For a substance with a toxic threshold, that is, a level below which there are no harmful health effects to

a group of people, setting a standard would involve determining a “no effects” threshold and

providing for a margin of safety. However, for

carcinogens, there is no known safe threshold.

Thus, providing an ample margin of safety as required by the statute might imply elimination of

all exposures by setting an emissions standard of

zero, or, possibly, a standard of no detectable

concentrations. For these situations, where EPA

determines that complete prohibition of emissions

would lead to “widespread industry closure” and

the costs of that closure would be “grossly disproportionate” compared to the benefits of reduced risk, EPA’s strategy has been to require

“emission reduction to the lowest level achievable by use of the best available control technology.” Recently, however, the D.C. Circuit Court

of Appeals ordered EPA to establish a safe level

of emissions for vinyl chloride based on health

considerations although EPA may consider cost

and technological feasibility to establish the actual emission standard (28,142).

In addition, EPA has taken the position that

it does not have to regulate exposures that present

an “insignificant risk. ” This policy has been challenged in a case concerning EPA’s failure to issue
106

benzene standards. The Natural Resources Defense Council (NRDC) argues that EPA must regulate hazardous air pollutants based exclusively

on public health considerations, not technology

and costs, and that EPA may not dismiss a health

risk by declaring it to be “insignificant” (145).

In the nearly 16 years since enactment of CAA,

EPA has listed seven carcinogens as hazardous air

pollutants and issued emission standards for six

carcinogens (see table 3-8): asbestos, 1973 (five

source categories—amended several times); vinyl

chloride, 1976 (two source categories); benzene,

1984 (for one source category, others pending);

radionuclides, 1985 (four source categories); and

arsenic (1986) (two source categories). Beryllium,

which is classified in the Annual Report on Carcinogens has also been listed and regulated, although not for carcinogenic effects.9 EPA has

listed coke oven emissions (1984), and proposed

emissions standards in March 1987, but has not

issued them in final form.

Although CAA provides EPA 1 year in which

to issue regulations on a pollutant after a substance is “listed,” EPA met this deadline only in

the case of vinyl chloride. From the date of listing to final action, however, EPA has taken an

average of almost 4 years for the six carcinogens

for which there are final rules. Four of these carcinogens were regulated or listed under legal pres-

‘Mercury is also regulated under the CAA, but is not classified

as a carcinogen.

sure: asbestos, vinyl chloride, radionuclides, and

arsenic (see table 3-8).

EPA has indicated an “intent to list” 10 substances: 1,3-butadiene, chromium, carbon tetrachloride, chloroform, ethylene oxide, ethylene

dichloride, cadmium, perchloroethylene, trichloroethylene, and methylene chloride. According

to EPA, an intent to list a substance as a hazardous pollutant does not legally bind the agency as

does a “listing” decision (296). This position was

challenged by NRDC in a pending suit (147).

NRDC contends that EPA is required to list a substance immediately if it has been determined to

cause serious irreversible illness and if EPA has

determined that it is a hazardous air pollutant

(42).

For the five substances regulated primarily for

carcinogenic effects, EPA has relied on human evidence of carcinogenicity (asbestos, vinyl chloride,

benzene, radionuclides, and arsenic). For 8 of the

10 substances EPA intends to regulate, it has relied on animal bioassays for evidence of carcinogenicity, and for 2 substances (chromium and cadmium), it has both animal and human evidence

of carcinogenicity.

EPA’s regulation of potentially hazardous air

pollutants has been criticized. A report by the

General Accounting Office noted that 4 of 37 hazardous substances identified for possible regulation in 1977 had been regulated by 1983 (198).

The report noted both delays in issuing regulations and in obtaining Science Advisory Board approval of EPA’s health assessment documents.

EPA REGULATORY ACTIONS UNDER THE CLEAN WATER ACT

First enacted in 1948, CWA has been amended

numerous times, most importantly in 1972, 1977,

1981, and 1987. The 1972 act set a goal of achieving “fishable, swimmable” waters by 1983 and for

prohibiting the discharge of pollutants and “toxic

pollutants in toxic amounts” by 1985, although

these deadlines were modified by the 1977 and

1981 amendments.

Toxic substances, including a number of carcinogens, have been regulated under CWA; but

the process has taken a long time, is not yet finished, and has featured considerable litigation.

The development of 65 water quality criteria documents for toxic pollutants has been an important part of EPA’s risk assessment activities. While

these are to be used by the States in developing

State water quality standards, few such standards

have actually been developed.

Under CWA, pollutors that discharge directly

into receiving waters must obtain permits (Na-
Table 3-8.—Carcinogens Considered for Regulation Under the Clean Air Act

--

Intent

Substance Type of evidence to list Listed NPRM Final

- -

-Industrial category — . .— —

—

High & low arsenic primary copper smelters, glass

manufacturing plants–(comment period extended &

reopened)

Asbestos mills, selected manufacturing operations,

spray-on asbestos materials, demolition operations,

surfacing of roadways with tailings

Maleic anhydride plants

Ethylbenzene/styrene plants

Storage vessels

Fugitive emissions from petroleum refining & chemical

manufacturing industries

Withdrawal of prop. stds–maleic anhydride, ethylbenzene styrene plants & storage vessels

Coke oven byproduct recovery plants

—

Petition/court action

Acrylonitrile d —

Arsenic

— — — —

Human — 6-05-80 7-20-83

—

8-04-86

4-06-73

—

—

6-06-84

6-06-84

4-73

—

—

.

—

—

—

—

—

—

—

—

4-17-85

2-6-85

—

4-26-74

10-21-76

—

Asbestos Human — 3-31-71 12-07-71 —

Human 6-08-77 4-18-80

12-18-80

EDF petition 4-14-77

American Petroleum Institute v EPA

(D D C )10-4-83

Benzene

12-19-80

1-81

—

3-6-84, NRDC petition denied

3-06-84 NRDC v EPA (D.D.C ) 1-27-84, Court required

EPA to publish final rule by 5-23-84

6-6-84

12-7-71

—

Berylliu m

b

Insuff. data but concerned

about potential

carcinogenicity

Animal–mice, rats

Human, animal, 1 species–rats

Animal, 3 species

Animal

Human, animal

Human, animal

Animal, 2 species–mice, rats

Animal

— 3-31-71 —

1,3-Butadiene

Cadmium

Carbon tetrachloride

Chloroform

Chromium

Coke oven emissions

Ethylene dichloride

Ethylene oxide

Methylene chloride

(dichloromethane)

Perchloroethylene

(tetrachloroethylene)

Radionuclidesc

10-10-85

10-17-85

8-13-85

9-27-85

6-10-85

4-26-82

10-16-85

10-2-85

—

—

—

—

—

—

—

—

—

—

—

—

—

Coke ovens

—

—

—

—

—

—

—

—

—

9-18-84 4-23-87

— —

—

Animal, 2 species–mice, rats 10-17-85 – – — —

Animal, 2 species–mice, rats 12-26-85 –

Human 4-11-79 12-27-79 4-6-83,

withdrawn

10-31-84

2-21-85

—

DOE facilities, NRC licensed & non-DOE Federal

facilities, elemental phosphorus plants & radon-222

from underground mines

Radon-222 from underground mines (control technique)

DOE facilities, NRC licensed & non-DOE Federal

facilities, elemental phosphorus plants

—

Sierra Club v. Ruckelshaus 84-0656, 2-17-84

(D.C.N.C.A )

7-25-84 Court order required Agency to take final

action within 90 days or find not hazardous

12-11-84 EPA held m contempt of Court, final

standards required within 30 days, 120 days

for radon-222 from underground mines

Trichloroethylene

Vinyl chioride

Animal, 2 species–mice, rats 12-23-85 – –

Human, animal, 3 Species– – – –

—

Emergency suspension of indoor aerosol pesticides

ethylene dichturlae-vinyl chloride plants & polyvinyl

chloride plants

—

—

rats. mice, hamsters 12-24-75 12-24-75 —

aTo be regulated through cooperative ventures with State and local governments (PilOt Pro)ect)

bBeVllium was regulated for non.carcinogeniceffects, however additional evidence which indicatespotential Carcinogenlciry IS Under review by EPA

CThe ~ropo~ed standards for rad, onuclldeswere wlthd~a~n followlng a court order which required EPA either to pfofnulgate the regulations within a speclfled period Of time or fl nd that the substances are

not hazardous arr pollutants EPA determined that “current practice provides an ample margin of safety to protect the publlc health from hazards associated with exposure to airborne radlonucl Ides” for

DOE facilities, NRC licensed & non-DOE Federal fac!litles & elemental phosphorus plants and issued an advanced notice of proposed rulemaklng for control techniques for radon-222 emlsslons from underground mines. After being held In contempt, EPA Issued final standards for the first three categories These standards were two and a half times higher than the originally proposed standards In order to

“accommodate the current level of emissions” (quoted in the Washington Post, Jan 1, 1985, p A6)

SOURCES: EPA response to OTA request and cited Federa/ Register notices
1 0 8

Table 3-9.—Carcinogens Considered for Regulation Under the Clean Water Acta

Number of States that

issued water quality

Toxic effluent standards

Type of standards Aquatic Human

Substance evidence Pro Dosed Issued life health Court actionb

Acrylonitrile . . . . . . . . . . . . . Human,

Aldrin/dieldrin . . . . . . . . . . .

Arsenic & compounds . . . .

Asbestos. . . . . . . . . . . . . . . .

Benzene . . . . . . . . . . . . . . . .

Benzidine . . . . . . . . . . . . . . .

Beryllium . . . . . . . . . . . . . . .

Carbon tetrachloride. . . . . .

Chloralkyl ethers . . . . . . . . .

Chlordane . . . . . . . . . . . . . . .

Chlorinated ethanes . . . . . .

Chloroform . . . . . . . . . . . . . .

Dichlorobenzidine . . . . . . . .

Dichloroethylenes . . . . . . . .

Dinitrotoluene . . . . . . . . . . .

Diphenylhydrazine . . . . . . . .

DDT . . . . . . . . . . . . . . . . . . . .

Halomethanes e 

. . . . . . . . . .

Heptachior . . . . . . . . . . . . . .

Hexachlorobutadiene . . . . .

Hexachlorocyclohexane . . .

Nitrosamines . . . . . . . . . . . .

Polynuclear aromatic

hydrocarbons . . . . . . . . . .

PCBS . . . . . . . . . . . . . . . . . . .

2,3,7,8-Tetrachlorodibenzop-dioxin (TCDD) . . . . . . . .

Tetrachloroethylene . . . . . .

Toxaphene . . . . . . . . . . . . . .

Trichloroethylene . . . . . . . .

Vinyl chloride. . . . . . . . . . . .

animal

Animal

Human

Human

Human

Human

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Animal

Human,

animal

—

12-23-73

6-10-76

—

—

—

12-23-73

6-30-76

—

—

—

—

—

—

—

—

—

—

12-23-73d

6-10-76

—

—

—

—

—

—

12-23-73

7-23-76

—

—

12-23-73

6-10-76

—

—

— — —

12-30-76 10/12 6/10

— 22 28

— — —

— — — c

1-12-77 3 4

— 7 4

— — — c

— — —

— — —

— — —

— — —

— — —

— — — c

— — —

— — —

12-30-76 — —

— — —

— 5 3

— — —

— 7 11 — — —

— — —

2-2-77 11 7 EDF V. EPA, 598 F.2d 62

(D.C. Cir. 1978)

— — —

— — —

12-30-76 — — Hercules v. EPA, 598

F.2d 91 (DC Cir. 1978)

— — — c

— — — c

%Jater Quality Criteria Documents were issued 11-28-80 for all substances listed except TCDD which was issued 2-15-84.

bAll substances listed are t. ~ regulated with te~hnology.based standards on an industry-by-industry basis as a result of a consent decree in NRDC V. ~fih 8 ERC.

The consent dacree was incorporated into the CWA 1977 Amendments, sec. 307.

CNRDC V. EPA NO. 85.1840 (D.c. Cir. filed 12-28-85); pertained to VOIMe organic chemicals.

dThe final rule was never promulgat~becauge EPA determined that there was insufficient evidence to promulgate responsible and defensible standards at the conclusion of a 1974 hearing.

eH~~@h~nes in cl u d e: chloromethane (methylchloflrje), bromometh~e (methyl bromide), dichloromethane (rMhylene chloride), bromodichloromethane, tribrorrlomethane

(bromoform), dichlorodifluoromethane and trichlorofluoromethane.

SOURCES: EPA response to OTA request for information including list summarizing water quality criteria documents and Federal Register notices cited in above response;

40 C Sec. 129 (1984).

tional Pollution Discharge Elimination System permit program (37 of 54 jurisdictions have been

(NPDES) permits) that delineate limitations on the approved). NPDES permits are based on the more

amounts of conventional pollutants (e.g., biologi- stringent of technology-based effluent limitations,

cal waste material) and toxic substances allowed State standards, or water quality criteria (166).

in discharges. NPDES permits are issued by EPA Indirect dischargers—industries that discharge

or by individual States that have an EPA-approved into municipal sewers—are not covered under
109

NPDES permits, but must comply with Federal

technology-based effluent limitations or local

limits established under federally approved

pretreatment programs. The pretreatment standards together with discharge limitations on publicly owned treatment facilities must achieve the

same amount of reduction of toxic pollutants as

would the use of effluent limitations on a direct

discharger.

From 1972 to 1975, EPA issued, under court

order, toxic effluent standards under section 307

for six pollutants: Aldrin/Dieldrin, DDT, Endrin,

Toxaphene, benzidine, and PCBS. While EPA had

thus begun to issue standards for toxic water pollutants on a pollutant-by-pollutant basis, several

environmental groups, thinking that EPA was not

regulating quickly enough, filed suit against EPA

for its failure to regulate toxic pollutants. At the

same time industry groups were concerned that

a pollutant-by-pollutant approach would require

different standards for different pollutants without regard for the availability or compatibility of

various strategies of control (79).

Under pressure from both groups, EPA developed a technology-based strategy for regulating

pollutants on an industry-by-industry basis. The

suits were settled in a consent decree (the “Flannery decree”) with EPA agreeing to place specific

“numerical limits on the quantities of 65 toxic pollutants in 21 industrial categories” (62,79). The

consent decree permitted EPA to regulate toxic

substances by means of those sections of CWA

designed to control ordinary nontoxic pollutants,

and to regulate pollutants on an industry-byindustry basis using effluent limitations (79).

Provisions of this consent decree were incorporated into CWA by Congress in the 1977

amendments, thereby giving congressional sanction to the development of technology-based regulations on toxic pollutants. One result is that under CWA, similar-sounding terms have different

meanings. An effluent standard is a control requirement based on the relationship between the

discharge of a pollutant and the resulting water

quality in a receiving body of water. An effluent

limitation, on the other hand, is a technologybased approach. For example, use of BPT, BAT,

or “best conventional technology, ” might be required for direct dischargers.

Effluent limitations are what are used today.

EPA has been in the process of issuing technologybased effluent limitations for 65 categories of toxic

substances.

The 65 classes of pollutants were chosen in the

negotiations leading to the consent decree. For

choosing these classes of pollutants, EPA assembled a working group of staff scientists from EPA

and other agencies (78). This group conducted a

literature search for toxic pollutants using several

criteria: 1) evidence that a substance posed potential carcinogenic, mutagenic, teratogenic effects, or adverse effects on any organ system; and

2) evidence of persistence, ability to bioaccumulate in organisms, and synergistic propensities.

These general criteria yielded 337 organic compounds, which the committee narrowed to 232.

Using the criteria of presence in water effluents

and evidence of carcinogenic, mutagenic, or teratogenic effects in animal tests or human epidemiology, or evidence of high toxicity to aquatic

organisms or systems, the list was further narrowed to 76. From this list of 76, EPA provided

more specific lists of 29, 18, and 18 classes of substances. 10

List I of 29 classes of substances satisfied three

criteria:

1.

2.

3.

they were known to occur in point source

effluents, in aquatic environments, in fish,

or in drinking water;

there was substantial evidence of carcinogenicity, mutagenicity, and/or teratogenicity

in human or animal studies; and

it was likely that point source effluents contributed substantially to human exposure, at

least locally.

List II of 18 compounds of second highest priority satisfied the first criterion, but toxicity evidence was based primarily on structural similarity

to compounds on list I, mutagenicity tests, or test

results that appeared to be incomplete or equivo10EPA originally developed a fourth list of 12 substances. Although

they are present in water effluents, they were judged to present a

less substantial direct hazard than the chemicals on lists 1-111 and

were not included in the final list of substances to be regulated.
110

cal. The 18 compounds on list III all satisfied the

first criterion, but there was no substantial evidence that these compounds have “primary carcinogenic, mutagenic, or teratogenic effects” (78).

(See table 3-10 for these lists.)

These 65 classes of pollutants, also known as

priority pollutants, initially contained more than

129 individual substances, but EPA developed a

list of 129 specific substances (177). Three of these

were removed from the list, leaving a total of 126

individual substances in 28 industrial classes for

which it had to set regulations.11

As of today, EPA has issued regulations for 26

of the 28 industry groups. Regulations for the

11The exact number of “industries” has varied because definitions

were changed.

pesticides industry had been issued, but that regulation was challenged in court, and EPA has remanded the regulation and initiated work to develop new regulations for the pesticide industry.

The organic chemicals, plastics, and synthetic

fibers industry has yet to be regulated, even

though it contributes the largest quantity of organic pollutants of any industry (224).

Moreover, the 28 industry groups do not cover

all industries that discharge pollutants. Important

industries, such as car washes and other commercial laundries, and paint and ink formulators are

excluded completely from effluent guidelines and

pretreatment standards. Certain subcategories of

other industries, such as adhesives and sealants,

are also exempted. Pretreatment standards (for

indirect dischargers) were proposed for some inTable 3-10.-Classes of Substances Regulated Under the CWA Consent Decree

List I List II List Ill

1.

2<

3.

4.

5.

6.

7.

8

9

10.

11.

12.

13.

14,

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Acenaphthene

Aldrin/dieldrin

Arsenic compounds

Asbestos

Benzene

Benzidine

Beryllium compounds

Cadmium compounds

Carbon tetrachloride

Chlordane (technical mixture and

metabolizes)

Chloroalkyl ethers

Chloroform

Chromium compounds

DDT and metabolizes

Dichlorobenzenes (1,2-,1,3-, and

4-dichlorobenzenes)

Dichlorobenzidine

Diphenylhydrazine

Heptachlor and metabolizes

Hexachlorocyclohexane

Lead compounds

Mercury compounds

Nickel compounds

Nitrosamines

Polychlorinated biphenyls (PCBS)

Polynuclear aromatic

hydrocarbons

2,3,7,8-Tetrach lorodibe nzo-p-d ioxi n

(TCDD)

Thallium compounds

Trichloroethylene

Vinyl chloride

1. Chlorinated benzenes (other than

dichlorobenzenes)

2. Chlorinated ethanes

3, 2-chlorophenol

4. Dichloroethylenes

5. 2,4-Dichlorophenol

6. 2,4-Dimethylphenol

7. Dichloropropane and

dichloropropene

8. Endosulfan and metabolizes

9. Endrin and metabolizes

10. Fluoranthene

11. Haloethers (not on list 1)

12. Halomethanes (not on list 1)

13. Hexachlorobutadiene

14. Naphthalene

15. Pentachlorophenol

16. Phthalate esters

17. Tetrachloroethy lene

18. Toxaphene

1. Acrolein

2. Acryionitrile

3. Antimony compounds

4. Chlorinated naphthalene

5. Chlorophenols (those not on list 11)

6. Copper compounds

7. Cyanides

8. Dinitrotoluene

9. Ethylbenzene

10. Hexachlorocyclo-pentadiene

11. Isophorene

12. Nitrobenzene

13. Nitrophenols

14. Phenol

15. Selenium compounds

16. Silver compounds

17. Toluene

18. Zinc compounds

SOURCE: Office of Technology Assessment.
111

dustries, such as textile mills, and plastics molding and forming, but were never issued (224).

The standards that have been issued cover the

list of 126 chemicals, although not all 126 chemicals are regulated in each of the 28 industry

groups. For each industry, EPA has issued regulations for the pollutants that it judged appropriate to regulate. In a given industry, a particular

chemical may not be present, may have no available treatment technique, may be too costly to

control, or maybe “incidentally” covered by regulations for other pollutants.

While the list of 126 chemicals has been the focal point of the regulation under CWA, many of

the chemicals found in industrial effluents are not

included in this list. In a nationwide study of

wastewater from a wide variety of industries and

publicly owned treatment works (POTWs), 4,000

wastewater samples were examined for organic

pollutants using gas chromatograph-mass spectrometry. The result is an overall picture of the

chemicals discharged by these industries and

POTWs. After ranking the top sO most frequently

occurring compounds, the researchers discovered

that 16 of them were priority organic pollutants.

Thus, 34 of the sO most frequently occurring compounds are not included in the EPA list of priority pollutants. For the industries studied, the distribution of pollutants differed by industry (i.e.,

what is important for one industry may not be

important in another industry). In general, the priority pollutants make up approximately 25 percent of the most frequently occurring compounds

(185).

In addition to setting the technology-based effluent limitations, EPA is also authorized to issue nonbinding water quality criteria documents

(under section 304) for substances that might pose

hazards to human health or the environment.

These are used to guide States in setting water

quality standards in their water courses (under

section 303) and as guidance for writing NPDES

permits. As of 1986, EPA had issued water quality criteria for 65 classes of priority toxic pollutants, including 29 determined to be carcinogenic.

These are listed in table 3-10,12

12The list of substances in the table was derived from a list EpA

provided that summarizes the water quality criteria documents. OTA

The water quality criteria documents present

information on protecting human health and

aquatic organisms (fish, shellfish, plants, etc.). For

human health, the criteria are developed to protect against noncarcinogenic risks as well as carcinogenic risks and are based on two potential

exposure pathways—through consumption of

drinking water and aquatic organisms. Because

safe thresholds for exposure to carcinogens have

not been established, the recommended criteria

for the maximum protection of human health are

water concentrations of zero. But EPA also prepared quantitative risk estimates for carcinogens.

The published criteria include the concentrations

of the chemical in water that corresponded to calculated lifetime cancer risks of 10-5

, 10-6, and

10-’.

States have the option of adopting these numerical criteria, but not all of them have actually done

so. Water quality criteria have been prepared for

the 65 classes of toxic pollutants covering 126

chemicals—the priority pollutants. For 37 of the

85 organic chemicals from this list, no States have

developed standards; for another 32, one State

has developed standards. Less than half of the

States have developed a water quality standard

for any single priority pollutant except arsenic for

which standards were established in 28 states

(345). Fourteen States have no water quality

standards at all for any of the priority pollutants

(224). As table 3-10 shows, seven of the water

quality criteria that identify chemicals as carcinogenic have been adopted by at least one State.

Although the environmental groups who brought

the original suit that resulted in the Flannery decree believed that regulating toxic pollutants by

means of technology-based effluent limitations

would speed the elimination of these from the Nation’s waterways, the regulation has taken considerable time. EPA has missed deadlines and has

requested eight separate deadline extensions from

the court. EPA’s most recent goal of regulating

all pollutants for all industries by January 1987

was not achieved. EPA now hopes to complete

included in the table only those substances that were indicated to

be carcinogens. Some substances that appear in the Annual Report

on Carcinogens have been regulated under CWA, but do not appear on this table because the water quality criteria were not based

on carcinogenic effects.
112

the effluent limitations specified in the original

1976 consent decree by September 1987 (166).

In addition, the compliance dates for the industries are usually 3 years after EPA publishes its

final rule on the BAT regulations. Thus, even

though the consent decree was issued in 1976, not

all industries will be in compliance with the regulations until the late 1980s or 1990.

Under the 1987 Amendments to CWA, each

State is required to submit to EPA a list of “toxic

EPA

The

hot spot waters.” These are areas where water

quality standards cannot be achieved or maintained because of toxic discharges after the currently required pollution controls have been implemented. The States must also submit a plan

to bring these areas into compliance with those

standards. The State water quality standards must

be based on EPA water quality criteria for toxic

pollutants.

REGULATORY ACTIONS UNDER THE SAFE DRINKING WATER ACT

Safe Drinking Water Act of 1974 regulates

the safety of water from public water systems, and

it contains several provisions that may be used

to regulate hazardous substances, including carcinogens in drinking water. SDWA authorized

EPA to regulate contaminants “which . . . may

have an adverse effect on the health of persons, ”

and prescribed several steps for EPA to follow.

First, EPA was required to publish national interim primary drinking water standards in 1975.

Second, Congress required that EPA commission

the National Academy of Sciences (NAS) to “conduct a study to determine . . . the maximum contaminant levels which should be recommended”

as national standards. NAS was also required to

update this information every 2 years. The NAS

study had to consider the impact of contaminants

on groups or individuals in the population who

are more susceptible to adverse effects than are

normal healthy individuals, exposure to contaminants in other media, synergistic effects of contaminants, and body burdens of contaminants in

exposed persons. In its 1977 report, Drinking

Water and Health, (134) NAS provided its first

list of contaminants (chosen on the basis of its

own criteria) that might have an adverse effect

on health and the levels at which those effects are

expected based on the best available scientific

knowledge. The NAS report, however, did not

provide recommended contaminant levels.

Third, within 90 days of the publication of the

NAS study, EPA was required to establish “recommended maximum contaminant levels (RMCLs)

for each contaminant which . . . may have any

adverse effect on the health of persons. ” Each such

RMCL was to be “set at a level at which . . . no

known or anticipated adverse effects on the health

of persons occur and which allows an adequate

margin of safety. ” RMCLs were nonenforceable

health goals which were then used as guidelines

for establishing enforceable drinking water

standards.

Once EPA established RMCLs for each contaminant, it was required to publish revised national primary drinking water regulations. These

regulations were enforceable health standards.

The required regulations were to specify a maximum contaminant level (MCL) or require the “use

of treatment techniques” for each contaminant for

which an RMCL is established. The established

MCLs were to be as close to the RMCLs as is “feasible. ” In determining feasibility, the Administrator could consider “the use of the best technology, treatment techniques and other means . . .

[that] are generally available [taking cost into consideration] .“

Drinking Water Standards

Under its authority to set drinking water standards, in 1975 EPA promulgated interim drinking

water standards for 10 inorganic and 6 organic

chemicals and for microbial contaminants (40 CFR

141.11-141.14). The interim drinking water standards issued in 1975 were based on the 1962 recommendations of the U.S. Public Health Service

(214).
113

Among the inorganic, arsenic was specifically

cited as being of concern because of carcinogenicity, although EPA decided that the evidence

for its carcinogenicity in drinking water was inconclusive. (See table 3-11 for a summary of these

data.) Among the organic compounds, endrin, lindane, and toxaphene were regulated based on the

effects of acute and chronic exposure, but the substances were later identified as carcinogens by the

NAS Drinking Water Committee and by EPA in

subsequent proposed drinking water standards.

In addition, EPA issued regulations for two

Table 3.11 .—Carcinogens Regulated and Proposed for

groups of carcinogens: radionuclides in 1976 (40

CFR 141.15) and for total trihalomethanes (four

chemicals) in 1979 (40 CFR 141.31).

Thus, the initial approach under SDWA was

to issue standards contaminant by contaminant,

specifying that every public water system monitor for each contaminant to ensure compliance

with the standard. However, it would be both

costly and technologically difficult to monitor for

relatively small amounts of many synthetic organic compounds and other potentially toxic conRegulation Under the Safe Drinking Water Act (SDWA),

Actions Before 1980

—

Substance Type of evidencea ANPR NPRM Final

Inorganics: b

Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Human, inconclusive — 3-14-75 12-24-75

Cadmium. . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Nitrate/nitrite . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Organics: c

Chlorinated hydrocarbons:

Aldrin/dieldrin. . . . . . . . . . . . . . . . . . . . . . — — d Not issued

Chlordane . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 Not issuede

DDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . – — Not issued

Endrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Heptachlor . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 Not issued

Heptachlor epoxide . . . . . . . . . . . . . . . . . — — 3-14-75 Not issued

Lindane . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Toxaphene . . . . . . . . . . . . . . . . . . . . . . . . — — 3-14-75 12-24-75

Total trihalomethanesf

Bromodichloromethane . . . . . . . . . . . . . Inadequate/ 7-14-76 2-9-78 11-19-79

suspected

Dibromochloromethane . . . . . . . . . . . . . Inadequate/ 7-14-76 2-9-78 11-19-79

suspected

Tribromomethane (bromoform) . . . . . . . Inadequate/ 7-14-76 2-9-78 11-19-79

suspected

Trichloromethane (chloroform) . . . . . . . Animal, 2 species 7-14-76 2-9-78 11-19-79

Radionuciides: (rats, mice)

Radium 226 & 228 . . . . . . . . . . . . . . . . . . Human, animal — 8-14-75 7-9-76

Gross alpha particle activation . . . . . . . Human, animal — 8-14-75 7-9-76

Beta particle & photon radioactivity. . . Human, animal — 8-14-75 7-9-76

Treatment standard for all

synthetic organic chemicais:g h

. . . . . . . 7-14-76 2-9-78 Withdrawn

aType of evidence was derived from the Federa/ Register notices that presented EPA’s rationale for regulatorY action.

bAccording to the NPRM, the MCLs for inorganic were based on the “possible effects Of iifetime eXpOSUre.” Specific carcinogenic concerns were cited only in response

to the comments on arsenic.

Carcinogenic evidence was not cited. The MCLS were based on the “effects of ~ute and chronic eXf)OSUre. ”

dcarcinogenicconcerns were mentioned but action was deiayed pending the reeults of a nationwide survey to determine the extent of drinking water contamination

by thes~ substances

ecarclnogenic concerns were mentioned but finai action was deiayed pending outcome of FIFRA Suspension/Cancellation proceedings.

fFormed as the resuit of chlorination Of drinking water.

gTreatment techniques were proposed for all synthetic organic chemicals (SOCS) as a ciass rather than individual MCLS because it was not considered feasible to

identify and monitor individual substances. Carcinogenic concerns were based on an NAS report, “Drinking Water and Health” which identified 22 SOCS (iisted below)

as known or suspected carcinogens.

hcou~ chailenge: EDF v, Cost/e, 11 ERC 1209, No. 752224, 2-10-78.

SOURCE: EPA response to OTA request and cited Federal Register notices.
114

taminants that might occur in drinking water coming from surface water sources. So in 1978 EPA

proposed treatment regulations for drinking water

systems that used surface waters. The focus was

on generic treatment techniques for all synthetic

organics without requiring monitoring of numerous individual contaminants.

The proposal for a treatment standard was

withdrawn, however, because EPA could not find

a clear basis for selecting communities with a synthetic organic chemical contamination problem

that would be required to use the treatment techniques. There was also concern about cost and

feasibility. Moreover, by 1980 emphasis shifted

from surface to ground water contamination. Because of this, EPA began again to focus on setting health standards using a contaminant-bycontaminant approach, rather than pursuing the

goal of setting treatment standards for surface

water (36).

The contaminants were grouped for the purpose of regulation into volatile synthetic organic

chemicals (VOCs), synthetic organic chemicals

(SOCs), inorganic chemicals, microbiological contaminants, radionuclides, and disinfectants. This

change in approach, from a contaminant-by-contaminant approach to surface water treatment

standards and back to the contaminant-by-contaminant approach, delayed the issuance of revised national primary drinking water standards.

In March 1982 EPA issued an Advance Notice

of Proposed Rulemaking (ANPRM) for nine

VOCs (303). It then held workshops around the

country and in June of 1983 issued proposed

RMCLs for VOCs (300). It issued final RMCLs

for VOCs and proposed MCLs for VOCs in November 1985 (301). Eight final MCLs for VOCs

were issued in June 1987 (322).

For 31 SOCs, 16 inorganic compounds (IOCs),

radionuclides, and microorganisms, EPA first issued an ANPRM in October 1983 (304), followed

by proposed RMCLa in November 1985 (302). Except for fluoride (which is not a carcinogen), EPA

has yet to issue final RMCLs, proposed MCLs and

final MCLs on these chemicals. In addition, EPA

must address a number of the 83 substances for

regulation under the requirements of the 1986

amendments.

To determine the RMCLs for carcinogens, EPA

classified substances into three categories based

on the evidence for carcinogenicity —strong evidence (Category I), equivocal evidence (Category

II), and inadequate evidence or lacking evidence

(Category III). Classification into these categories

for the drinking water standards is based largely

on the the classification of the substance in the

EPA weight-of-evidence classification (see ch. 2).

Category I chemicals have strong evidence for

carcinogenicity from either human or animal

studies, i.e., weight-of-evidence group A (sufficient evidence for human carcinogenicity) or

group B (probable human carcinogen, based either on limited human evidence or sufficient animal evidence). Category I substances have RMCLs

of zero. EPA chose this level for RMCLs based

on the legislative history of SDWA (301). MCLs

for Category I substances must be set as close to

zero as is feasible, taking costs into consideration.

Category II chemicals, with equivocal evidence

for carcinogenicity for purposes of drinking water

standards, are chemicals including weight-ofevidence group C (possible human carcinogens

based on limited evidence in animals). Category

III chemicals, those with inadequate evidence or

lacking evidence for carcinogenicity, are from

weight-of-evidence group D (not classified or inadequate animal evidence) or group E (no evidence for carcinogenicity).

Category II substances have RMCLs set in one

of two ways. The first, and preferred approach

is to set the RMCLs based on noncarcinogenic

chronic toxicity data. Under this approach, EPA

calculates an Adjusted Acceptable Daily Intake

(AADI). The second method, used when adequate

chronic toxicity data are lacking, is to base the

RMCLs on the results of quantitative risk assessment using the limited animal carcinogenicity data

with the risk level set in the range 10-5 to 10-6.

Category 111 substances have RMCLs based on

noncarcinogenic chronic toxicity data. Again EPA

calculates an AADI.

For either Category 11 or Category III chemicals,

EPA determines, on the basis of chronic toxicity

data, a highest “no observed adverse effect level”

(NOAEL) (expressed in mg/kg body weight/day),
1 1 5

divides that figure by an appropriate “uncertainty”

or “safety” factor (explained below), then multiplies this figure by the assumed weight of an adult

(70 kg) and divides by the assumed amount of

water consumed by an adult (2 liters/day). The

result is an AADI:

AADI = (NOAEL/uncertainty factor) (70kg/2Liters/day)

A safety or uncertainty factor of 10 is “used

with valid experimental results on appropriate durations of exposure in humans. ” A safety factor

of 100 is “used when human data are not available and extrapolating from valid results of longterm studies in animals” is involved. A safety factor of 1,000 is “used when human data are not

available and extrapolating from studies in animals of less than chronic exposure. ” Finally, an

additional uncertainty factor between 1 and 10

is used when EPA has to use a “lowest observed

adverse effect level” (LOAEL) rather than a

NOAEL (151,299).

Since Category 11 substances have some limited

if insufficient evidence of carcinogenicity from

animal studies, EPA introduces additional safety

or uncertainty factors to account for the equivocal evidence of carcinogenicity. Normally, a safety

factor of 10 is used, but if data indicate the need

for a greater or lesser safety margin, other uncertainty factors can be used (301). In general EPA

is more cautious in setting RMCLs and MCLs for

Category II substances than for Category III substances.

In its regulatory proceedings so far, five of the

nine VOCs were identified as probable carcinogens (Category I). EPA’s decision to consider one

of them, 1,1-dichloroethylene, as belonging to category 11 was legally challenged by NRDC and a

decision is pending (158). Of 32 SOCs, 10 are

probable carcinogens. Of the inorganic substances, two (arsenic and asbestos) were placed

in Category II. These substances are carcinogenic

when inhaled. EPA has concluded, however, that

there is little evidence indicating that asbestos is

carcinogenic in drinking water. There is evidence

that drinking water exposures to arsenic are associated with skin cancer, although it appears that

this is true only for the generally nonfatal forms

of skin cancer (36). For the 15 Category I chemicals, 2 were based on human data, and the balance on animal evidence. In addition, all the radionuclide standards were based on human data

(see table 3-12).

Health Advisories

In addition to legally binding regulations, EPA

has also provided nonbinding health advisories

for contaminants in water. In 1980 the National

Academy of Sciences began providing EPA with

“suggested no adverse response levels” (SNARLS)

for contaminants. These contained acute (24-hour

exposure) and short-term (7-day exposure) toxicity information as well as chronic toxicity information. The Office of Drinking Water developed its own SNARLS and issued drafts of them

beginning in 1981. Subsequently the term SNARLS

was changed to “health advisories” (HAs).

HAs are approximately 10-page dossiers on

chemicals that give some indication of their occurrence, their use, short-term toxicity information,

chronic toxicity information (including contaminant levels calculated to be associated with different levels of risk, e.g., 1 case per 10,000 people

exposed, 1 case per 100,000 people, 1 case per 1

million people), analytical methods of detecting

them, and treatment methods that operators of

municipal water systems can use. Health advisory

concentration numbers are “developed from data

based on non-carcinogenic endpoints of toxicity.”

For suspected carcinogens “non-zero l-day, 10-

day and longer-term health advisories may be derived . . . [but] lifetime exposures may not be recommended. ” In addition, “projected excess lifetime cancer risks are provided to give an estimate

of the concentrations of the contaminant which

may pose a carcinogenic risk to humans. ” These

estimates are presented as “upper 95 percent confidence limits derived from the linearized multistage model which is considered to be unlikely

to underestimate the probable true risk” (325).

EPA issued its first HAs in 1979, reevaluated

them in 1985, and rereleased some 52 for public

comment and for evaluation by the EPA Science

Advisory Board (36). Health advisories are not

legally binding, but are intended to advise public water systems about the health effects of chemicals and their treatment. Health advisories have

been widely used in the water industry to determine responses to contamination incidents (36).
116

Table 3-12.—National Primary Drinking Water Regulations (NPDWR) for Carcinogens, Actions After 1980

Recommended maximum Maximum contaminant

EPA classification & contaminant level (RMCL) level (MCL)

Substance type of evidence ANPR NPRM FinaI NPRM Final

Inorganics (not regulated as carcinogens) :

Arsenic a. . . . . . . . . . . . . . . . . . . . . . II

Asbestos . . . . . . . . . . . . . . . . . . . . . II

Cadmium . . . . . . . . . . . . . . . . . . . . . Ill

Chromium . . . . . . . . . . . . . . . . . . . . Ill

Lead . . . . . . . . . . . . . . . . . . . . . . . . . Ill

Nitrate/nitrite . . . . . . . . . . . . . . . . . . Ill

Selenium . . . . . . . . . . . . . . . . . . . . . Ill

Synthetic organics:

Acrylamide . . . . . . . . . . . . . . . . . . . I, animal

Alachlor . . . . . . . . . . . . . . . . . . . . . . I, animal

Chlordane . . . . . . . . . . . . . . . . . . . . I, animal

Dibromochloropropane (DBCP) . . I, animal

1,2-Dichloropropane . . . . . . . . . . . . III animal

Epichlorohydrin . . . . . . . . . . . . . . . I, animal

Ethylenedibrornide . . . . . . . . . . . . . I, animal

Heptachlor . . . . . . . . . . . . . . . . . . . . I, animal

Heptachlor epoxide . . . . . . . . . . . . I, animal

Lindane . . . . . . . . . . . . . . . . . . . . . . II, animal

Monochlorobenzene . . . . . . . . . . . Ill

Polychlorinated biphenyls

(PCBs) . . . . . . . . . . . . . . . . . . . . . I, animal

Styrene. ... ... ... ... .. ....... Ilb

Toxaphene . . . . . . . . . . . . . . . . . . . . I, animal

Volatile organic compounds:

Benzene . . . . . . . . . . . . . . . . . . . . . . I, human

Carbon tetrachloride . . . . . . . . . . . I, animal

p-dichlorobenzene . . . . . . . . . . . . . Ill, animal

1,2-Dichloroethane . . . . . . . . . . . . . I, animal

1,1-Dichloroethylene . . . . . . . . . . . II, animal

Tetrachloroethylene . . . . . . . . . . . . II, animal

1,1,1 -Trichloroethane . . . . . . . . . . . Ill, animal

Trichloroethylene . . . . . . . . . . . . . . I, animal

Vinyl chloride . . . . . . . . . . . . . . . . . I, human, animal

Radionuclides:

Radium 226 & 228 . . . . . . . . . . . . . Human

Gross alpha particle activation . . Human

Beta particle & photon

radioactivity. . . . . . . . . . . . . . . . . Human

Uranium . . . . . . . . . . . . . . . . . . . . . . Human

Radon . . . . . . . . . . . . . . . . . . . . . . . . Human

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

—

—

—

—

10-5-83

—

—

—

10-5-83

3-4-82

—

3-4-82

—

3-4-82

3-4-82

3-4-82

3-4-82

10-5-83

10-5-83

10-5-83

10-5-83

10-5-83

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11.13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

6-12-84

6-12-84

6-12-84

6-12-84

6-12-84

6-12-84

6-12-84

6-12-84

6-12-84

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85

c

11-13-8 5

11-13-85

11-13-85

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

11-13-85

11-13-85

11-13-85

11-13-85

11-13-85 —

11-13-85

11-13-85

11-13-85

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

~he proposed regulation was not based on carcinogenic effects because it was considered also to have potential nutrient value.

bpropo9ed regula~ion not based on carcinogenic effects.

ccomment period reopened to consider new data, 11-13-W

SOURCES: EPA response to OTA request and cited Federal Register notices.

Regulation of carcinogens in drinking water has

been slow. The SDWA was passed in 1974. As

indicated above, in 1975 interim standards based

on Public Health Service recommendations of

1962 were issued, and later radionuclides (1976)

and trihalomethanes (1979) were regulated. These

standards are still in effect today.

As of June 1987, EPA has issued eight final

MCLS that constitute national revised primary

drinking water standards. Revised HAs designed

to provide operators of public water systems with

guidance concerning health risks from potential

toxic substances are not yet final, although they

are under development.

The 99th Congress, concerned that drinking

water standards were not being set quickly

enough, set regulatory deadlines in the 1986 reauthorization of SDWA.
1 1 7

The 1986 SDWA amendments (Public Law 99-

339) required EPA to regulate 83 chemicals in

drinking water that the agency had identified as

candidates for regulation in 2 ANPRMs in 1982

and 1983 (303,304). The list of 83 are to be regulated in 3 stages by 1989 and include 51 in the

process of regulation. EPA must also add 25

chemicals to the list every 3 years after 1989.

According to EPA staff, this list of 83 included

numerous substances that EPA had not otherwise

intended to regulate because of low toxicity or low

occurrence in drinking water (36).

The 1986 amendments gave RMCLs a new

name: Maximum Contaminant Level Goals

(MCLGs). The criteria for these remain the same

as for the RMCLs. In addition, MCLs must now

be proposed at the same time as the MCLGs rather

than in two stages as they were previously. The

MCL must be as close to the MCLG as is feasible

using the BAT, taking costs into consideration.

It must be at least as low, however, as would be

achieved using granulated activated carbon (an

especially good technique for removing organic

contaminants). When an MCL is exceeded, the

public must now be notified within 14 days of the

detection of the violation.

In addition, the amendments required EPA to

develop a list of unregulated contaminants which

water utilities must monitor at least once every

5 years. A list of 50 unregulated chemicals for

which monitoring will be required is scheduled

for publication in June 1987 (36). Congress also

authorized stricter enforcement of SDWA and increased fines for violations.

EPA REGULATORY ACTIONS UNDER FIFRA

The Federal Insecticide, Fungicide, and Rodenticide Act was substantially amended in 1972.

Under this act, EPA is to screen pesticides through

the registration process before they enter commerce and reregister pesticides that were on the

market before 1972 to prevent unreasonable adverse health and environmental effects. In both

cases, EPA may require manufacturers to submit

testing results for product and residue chemistry,

environmental fate, and tests in fish, wildlife, and

mammals, including long-term bioassays for carcinogenicity.

An applicant for registration of a pesticide must

file with EPA certain required information, including a statement of all claims made for the pesticide, directions for its use, a description of tests

made upon it, the test results used to support

claims made for the substance, and appropriate

toxicity data for each pesticide. Specific testing

requirements depend on the expected use pattern.

EPA now requires carcinogenicity testing in two

species for all food use pesticides (40 CFR 158).

In general, EPA must register a pesticide if “it

will perform its intended function without unreasonable adverse effects on the environment”-

which are defined as “any unreasonable risk to

man or the environment, taking into account the

economic, social and environmental costs and

benefits of the use of any pesticide. ” The burden

of proof to establish the safety of a product lies

on the person who wishes to register and market

the product.

If EPA finds that a registered pesticide meets

or exceeds certain criteria for risk, a special review may be initiated. (Prior to 1983, this was

called a “Rebuttable Presumption Against Registration” (RPAR). ) This in-depth review of the risks

and benefits of the pesticide use determines what

regulatory action, if any, is appropriate. The 1975

amendments to FIFRA require that if involuntary

regulatory measures are proposed, the EPA recommendations must be submitted to the Department of Agriculture for comment and to the FIFRA

Scientific Advisory Panel for review. There is also

an opportunity for public comment throughout

this process. The outcome of a special review can

range from no action, to an immediate emergency

suspension, to cancellation of the pesticide. Actions may also consist of modifying the use pattern of the pesticide.

Unless the data on which the special review or

RPAR is based are shown to be unreliable or invalid, or the estimated benefits of continued uses
1 1 8

outweigh the estimated risks, FIFRA provides for

cancellation or suspension of their registration.

In 1972, there were about 50,000 pesticide products and 600 active ingredients already on the

market that required reregistration under the new

law. Many of the problems of regulating pesticides have arisen with these pesticides. The aim

of reregistration was to identify missing information about pesticides, to require registrants to supply it, and to reevaluate the safety of the chemicals in light of the new information. Reregistration

involves a number of steps:

1.

2.

3.

4.

5.

EPA requests certain pivotal studies on the

chemical from the registrant (“data call-in”)

if studies have not yet been submitted. Data

requirements are based on EPA regulations

(40 CFR 158). Since 1980, EPA has required

carcinogenicity data for reregistration where

required (40 CFR 158).

EPA reviews all available data on the chemical, including that requested in the data

call-in.

EPA issues a “regulatory position document”

(“registration standard”) which summarizes

the science position, changes in use necessary to reduce risk, and additional data gaps.

Registrant either agrees to fill data gaps or

action may be initiated to withdraw the

chemical from the market.

If “significant risk triggers” are identified in ——

steps-2 through 4, a special review is initiated (21).

The reregistration of active ingredients has

taken much longer than originally anticipated.

The process was initially to be completed by 1976,

but in 1975 Congress extended that deadline to

1977, and in 1978 dropped the deadline completely because of the large number of substance

reviews outstanding (203).

The EPA data files for most of the pesticides

needing reregistration are still incomplete, although

information is currently under development. EPA

conducted a data call-in for approximately 600

active ingredients subject to reregistration. As a

result of data call-ins, by March 31, 1986, 61 active ingredients had been canceled voluntarily,

withdrawn, or suspended, and 124 interim registration standards developed. Of these 124 active

ingredients with registration standards, 6 were

voluntarily withdrawn, while 12 were beginning

special reviews, and 17 were ready for final regulatory review, while 89 registrants’ responses

were in progress. One active ingredient is undergoing final standard processing, which would result in final reregistration (203).

Thus, for 72 percent of the chemicals reviewed

sufficiently to develop registration standards (89

of 124), EPA is currently waiting to obtain necessary data. Beyond this, over two-thirds of all

active ingredients (415 of 600) have not yet been

reviewed sufficiently for the agency to issue even

registration standards.

Of the 600 active ingredients, about 390 are

used on foods. EPA has completed its data callin for all 390 substances and has issued interim

registration standards on 92, with approximately

300 yet to be evaluated. EPA lacked sufficient information to judge the carcinogenic effects of 57

of these 92 ingredients (203).

Actions on Pesticides Already

Identified as Carcinogenic

For some 80 active ingredients that have been

voluntarily removed from the market or subject

to some regulatory activity, carcinogenicity has

been an important element. In all, 65 of these 80

substances (81 percent) have had carcinogenic effects.13

OTA requested information from EPA on the

pesticides it has identified as carcinogenic. As of

March 31, 1986, it had identified at least 81 carcinogens. (See tables 3-13 to 3-16 for a summary

of these data. )14 These carcinogens were identified through testing results obtained from a variety of sources, including manufacturers and NTP,

and reported in the open literature.

● Of the 81, 18 have been canceled or restricted

for some or all uses as a consequence of EPA

action (table 3-13).

13The percentages are based on the information in “Report on

the Status of Chemicals in the Special Review Program, Registration Standards Program, and Data Call-in Program” (331).

14ThiS count of chemicals is slightly different from that in other

sources of information, including EPA status reports, GAO reports,

and correspondence between EPA and Congressman Waxman.
119

●

●

●

Ž

For one, Daminozide (Alar), EPA published

a notice of intent to cancel, but the chemical

is still undergoing review (table 3-13).

Fifteen pesticides have been voluntarily canceled by the registrant (table 3-14).

At present, 18 of these substances are in special review (SR) (table 3-15). For 10 carcinogens, the SRs have been completed but the

chemicals have not been suspended or canceled because EPA decided to allow their continued use based on the balance of risks and

benefits (104). For the remaining eight substances, SRs have yet to be completed.

EPA has identified 29 carcinogens for which

it has not started an SR or cancellation proceeding (table 3-16). Of these, 24 are food

use pesticides.

Tables 3-15 and 3-16 together indicate that EPA

has identified 47 carcinogenic pesticides that have

not been canceled. Of these, 18 were made the

subjects of SRs (10 completed, 8 still in progress);

for others, EPA has decided not to conduct an

SR. For example, for 13 of the 47, EPA has determined that either low exposure or risk or the

weight of the evidence for carcinogenicity suggest

no action need be taken. The remaining identified carcinogenic pesticides are still in use, although EPA suggested to OTA that for many of

these regulatory action has been taken to reduce

exposure (21). These actions may consist of requiring lowered application rates, enclosed application systems, extension of reentry intervals, a

ban on aerial application, and protective equipment and clothing (104).

Moreover, “cancellation” of the 18 chemicals

on table 3-13 does not mean that the chemical is

no longer in use. Often, a cancellation is for particular uses, while other uses continue. For example, chlordane was canceled in 1978 for food use

(table 3-14), but continues in use for termite control. EPA is currently considering whether to cancel that use as well.

For the 18 substances that have been canceled

or restricted by EPA (table 3-13), the average time

carcinogens were in SR was 44 months, with the

shortest time being 13 months and the longest 88

months. Substances in SR earlier took the shortest time with more recent cancellations taking

longer. For 10 carcinogens in SR, but not suspended or canceled, the average length of the SR

was 63 months, with the shortest SR 36 months

and the longest 106 months.

Where EPA has acted on carcinogenic pesticides, the evidence for carcinogenicity has generally been based on positive results from at least

two animal species (tables 3-13 to 3-16).

According to figures in a recent NAS report

(136), of 289 food use pesticides, 53 or approximately 18 percent have been determined by EPA

to beat least potentially carcinogenic. However,

for many of these the data are still incomplete or

have not been evaluated. Food use pesticides raise

special issues with regard to coverage under

FDCA.

For raw agricultural commodities, a tolerance

for pesticide residues is based on the consideration of risks and benefits (under sec. 408 of

FDCA). If processing the food leads to an increase

in the concentration of the pesticide residue to a

level above that found in the parent raw commodity, then the Delaney clause applies (sec. 409

of FDCA). In this case, the residue is deemed to

be a food additive and may not be added to food

if it is determined to be carcinogenic. Congress

specifically exempted processed food from the

Delaney clause if the residue level is no higher than

is found in the raw commodity. For commodities that are processed, if no section 409 tolerance

may be granted, EPA will not grant a 408 tolerance for the raw commodity either.

While the Delaney clause has been consistently

used to deny new tolerances for active ingredients,

it has never been used to revoke an existing tolerance. Prior to 1978, section 408 tolerances were

generally established without any oncogenicity or

residue data. Few of the pesticides approved before 1978 have tolerances for residues in processed

foods. Where no tolerance exists for a processed

food, EPA simply assumes that residue levels are

the same as the level permitted in raw commodities. In the report, the NAS committee concluded

that there is no scientific justification for the regulatory distinction between raw and processed

foods. The committee also found no scientific

justification for the inconsistency between the

safety standards applied to old and new pesticides

(136).
120

L

- L

I I

I

I

I

I I

I I

I

I

I I I I

I I

I

I

I

I

I

I

I

I

I

I

I

I

I

I I I I

I I
Table 3-13.—Fl FRAa

1. Canceled and Restricted Carcinogenic Pesticides—Continued

Special

Registration Type of review Proposed

Substance standard evidence initiated determination

Endrin —

Goal e (product of oxyfluor- –

fen, contaminated with

PCE)

Mirex —

Pentachlorophenol e (con- ‘–

taminated with Dioxin)

Pronamide (Kerb) 4-86

Toxapheneb c —

2,4,5 -T/Sllvex —

Animal,

2 species

Animal, 2

species

Animal,

2 species

Animal

Animal 1

species—

mice

Animal, 5

species–

rats, mice,

dogs, monkeys,

hamsters

Animal, 2

species

7-27-76

1-80

—

10-18-78

5-20-77

5-25-77

4-21-78

11-2-78

6-23-82

—

7-13-84

wood use,

12-12-84

non wood

uses

1-15-79

11-29-82

12-13-79

Notice of Intent Voluntary cancellation/ Comments/other Court action or

to cancel/suspend some or all uses regulatory action administrative hearing

.. ——.. -—

7-25-79 most uses

6-23-82

3-18-71, 9-23-76 cane

all uses

7-13-84 wood uses

10-26-79

11-29-82

3-15-79 susp. some

uses, 1-2-85 susp, all

uses

10-24-84 0ther uses –

— Limited concentration of

PCE

— 5-3-72 Iabeling restrlctions, 6-30-72 reinstated

registrations under certain

conditions, 4-4-73 modified ban on aquatic application

— Labeling & restricted use

requirements

— Restricted use & Iabeling

required

—

Canceled for most uses

—

—

—

Allied Chemical Co., FIFRA Doc

#293, 10-20-76, re. cancellatlon–

2-12-76 registrant submitted phaseout plan to settle hearing, McGI// v

EPA, 593 F.2d 631 (5th Cm. 1979)

In re. Chapman Co et al , FIFRA

Doc #529, 7-15-84, re Cancellation

—

.

In re: Dow Chemical Co , et al ,

FIFRA Dec. #409/410, re. emergency suspension, FIFRA Doc #415, re

cancellation, 3-1-79; Doc C/7ernma/

Co v B/urn, 469 F, Supp. 892 (E D

Mich. 1979)

aThese tableS ~onta, n only ~ctlve ~eStlclde ,ngred,entS In add,tlon to the Ilsted substances, EpA has ldentjfled 28 Inerf Ingredients Of concern for potenflal carclnogenlcdy among 55 Ineffs Of concern for Inherent foxlclty (as Of 6- 19-85) The agency

IS evaluatma these Inerfs to determme the extent of use and exI)osure whether thev are essenhal whether safer alternatives are avaflable, and what regulatory actions would be appropriate The 28 Inert Ingredients of carclnoqeruc concern are–amhne

dlethylhexy~hthalate (DH+P) asbestos benzene, betabutyrolactone cadr?wn compounds carbon tetrachlorlde chlorobenzene chloroform 1 2.dtchlorojropane dlmethyi 1 1 hydrazme 1 2 dloxane eplchlorohydrtn ethylene d;chlorlde ethylene thlourea

formaldehyde hexachlorophene hydrazlne Isophorone methylene chlarlde 2-nltro-propane perchloroethylene phenylphenol propylene oxide rhodamlne thiourea 1 1 1 -trl-chloraethane (methyl chloroform) lrlchloroethylene

bRegulafed under Sec 408 FDCA Registered for food uses–tolerances estabhshed for pestlclde uses on raw a9rlcultural commodities

CRegulafed under ~laney clause of FDCA Sec 409(c)(3)(A) A food ,aCjdltlve lolerarl~e IS required when [he pestlclde residue level In pracessed food IS greater than the tolerance level for the raw agrlculfural commod[ty but may not be established

for carcinogenic peshcldes

dAccordlng t. EpA these compounds d. not have on~ogenfc effects bul they have a metabohte that has shown OnCOgenlC effeCtS In anlMalS

eAccardlng t. EpA these compounds do not have Oncogenlc effects but they contain a contaminant that has shown oncogenlc effects In ammals

SOURCE EPA response to CITA request and cited Federa/ RegLs7er notices
Table 3-14.—FlFRAa

Il. Voluntary Cancellations of Carcinogenic Pesticides

Special

Registration Type of review Proposed Notice of intent Voluntary cancellation/ Comments/other Court action or

Substance standard evidence initiated determination to cancel/suspend some- or all uses regulatory action administrative hearing

Acrylonitrile — Animal – — — 9-1-76 3 products —

Benzene — Human – — — 7-31-85 All products

BHC — Animal, 10-19-76 10-19-76 — 10-19-76, manufacturing 7-21-78 amended registra- —

2 species only, began to import tion to replace non-gamma

Isomer content with

Lindane

Carbon tetrachloride – Animal, 10-15-80 – — 9-5-83 —

2 species

—

Chloranil — Animal – — — 1-19-77 — —

Erbon — Animal – — — 10-4-80 — —

Maleic hydrazideb c– Animal, 10-28-77 6-28-82 ter- — 11-81 some uses Returned to registration —

1 species– minated process

mice

Monuron 6-83 Animal – — — 8-16-77 Tolerance revoked m 1973 —

Nitrofen (TOK) — Animal – — — 9-15-83 — —

OMPA — Animal – — — 5-28-76 . .

Perthane — Animal – — — 6-20-80 — —

Safrole — Animal – — — 2-25-77 — —

Strobane — Animal, – — — 6-28-76 All products —

1 species

2,4,5 -Trichlorophenol – Animal 9-15-78 12-31-85 — All uses, no date — —

Trysben — Animal – — — 2-9-78 — —

aTheSe tables corltaln only active pestlclde Ingredients in add!tlon to the hsted substances, EPA has !dentlhed 28 inert mgredlenls of concern for polentlal Carclnogemclty among 55 Ineris Ot COnCern fOr Inherent foxlcl!y (as of 6-19-85) The a9encY

IS evaluating these merfs to determme the extent of use and exposure, whether they are essential whether safer alternates are avadable, and what regulatory actions would be appropriate The 28 inert Ingredients of carclnogen!c concern are—amhne

dlethylhexylphthalate (DEHP), asbestos, benzene, betabufyrolactone, cadmium compounds, carbon tetrachlonde, chlorobenzene, chloroform, t ,2-dlchloropropane, dlmethyl 1,1 hydrazme 1,2 dloxane eplchlorohydrm, ethylene dlchlonde, ethylene thlourea

formaldehyde, hexachlorophene hydrazme Isophorone, methylene chloride 2-nKro-propane, perchloroethylene, phenylphenol, propylene oxide rhodamme thlourea 1 1 I-tn-chloroethane (methyl chloroform) trlchloroethylene

bRegulated under Sec 408 FDCA Reglstererj for food uses–tolerances established for pestlclde uSeS on raw a9rlcultural commodities

cRegulated under Delaney Clause of FIXA Sec 409(c)(3)(A) A food addltlve tolerance IS requwed when the pestlclde residue level m processed food IS greater than the toieraflce level fOr the raw a9rlcultural commodity but maY not be established

for carcmogentc pesticides

SOURCE EPA response to OTA Request and cited Federd Register notices
Table 3-15.—FlFRAa

Il. Carcinogenic Pesticides in Special Review

(A. Presently under review)

Court action or

administrative hearing

—

—

—

—

—

Special

Registration Type of review Proposed Notice of intent Voluntary cancellation/ Comments/other

Substance standard

Alachlor b

11-21-84

evidence initiated

Animal, 1-9-85

2 species

determination to cancel/suspend

— —

some or all uses regulatory action

Labeling requirement, restricted use

— Labeling requirement,

restricted use

Amitrole 3-30-84 Animal 6-15-84 — —

Cadmium — Animal, 10-26-77

human

Animal, 12-9-84

2 species

Animal, 2 8-18-80

species

— — — —

Captafol b

10-84 — Labeling requirement;

restricted use

Captan b c 3-86 6-21-85 —

proposed determination

—

— —

Ethylene oxideb ., – Animal– 1-27-78

insufficient

but positive

short-term

test (in

1978)

— — —

Kelthane (Dicofol)b

(contains DDT) ., 12-83 Animal, 1 3-21-84

species–

mice (see

DDT)

10-10-84,

proposed

cane.

— — — —

Linuronb

7-84 Animal, 2 9-26-84 — — Labeling requirement

species

aThese tables Contain ~nly ac~lve ~es~lclde ,ngre~len~s in ~ddltlon t. the lls~ed substances, EpA has ,dentltlecj 28 Inert ln~redients of concern for potential carclnogenlclty among 55 Iflerfs Of concern for Inherent toxlclty (aS Of 6-19-85) The a(JenCy

IS evaluating these Inerts to determme the extent of use and exposure, whether they are essential, whether safer alternates are available, and what regulatory actions would be appropriate The 28 inert mgredlents of carcmogeruc COflCEmWe-afllllfle

dlethylhexylphthalate (C) EHP), asbestos, benzene, betabufyrolactone, cadmium compounds; carbon tetrachlorlde. chlorobenzene; chloroform, 1,2-dlchloropropane, dimethyl 1,1 hydrazme 1,2, dioxane: epichlorohydrin, ethylene dlchlorlde, ethylene thlourea

formaldehyde, hexachlorophene hydrazlne, lsophorone, methylene chloride, 2-nttro-propane, perchloroethylene, phenylphenoi, propylene oxide, rhodamine, thlourea, 1,1,1 -trl-chloroethane (methyl chloroform), frlchloroethylene

bRegulafed under Sec 408 FOCA Registered for food uses–tolerances estabhshed for Pestlclde uses on raw a9rlcultural commodities

CRegulated under ~laney clause of F~~A sec 409(c)(3)(A) A food addifive tolerance ,s ~equlred when the pesticide residue level in processed food IS greater fhan the tolerance level for fhe raw agrlcuttural commodity but May nof be established

for Carclnogeruc pestlctdes

SOURCE EPA response to r)TA request and cited Federa/ r?egNer nollces
Table 3-15.—FlFRAa

Ill. Carcinogenic Pesticides in Special Review

(B. Special review complete but substance not suspended or canceled)

Special

Registration Type of review

Substance standard evidence initiated

Proposed Notice of intent Voluntary cancellation/ Comments/other

determination

Court action or

to cancel/suspend some or all uses regulatory action administrative hearing

Benomyl b c 4-86 Animal, 1

species—

mice

Animal

Animal, 2

species

Animal, 2

species

Animal, 2

species

Animal, 1

species

Animal, 1

species

Animal,

insuff

Animal, 1

species—

mice

12-6-77

4-6-76

5-31-77

9-22-77

8-10-77

1-4-84

2-18-77

10-13-77

12-7-77

8-30-79

10-20-82 — — Labeling requirements;

restrictions on conditions

of application

—

Chloroform

(trichloromethane) 12-82

3-83

3-31-83

—

—

9-85

12-82

terminated

SR

6-23-82

More data required,

exposures reduced with

label changes

—

Diallate b

Labeling requirements,

training & protective

clothing

— —

—

—

—

—

— —

—

—

Dimethoate

EBDCs b c

Ethalfluralinb

Lindaneb

1-19-81

10-27-82

1-4-84

9-30-83

—

—

—

— —

More data required, label- —

ing requirement

Tolerances issued, protective clothing requried

More data required,

restricted use

In re: Happy Jack Inc. & Continental

Chemist Corp. FIFRA Doc. #524 &

526, 10-19-83, re: cancellation

PCNBb4-28-82

terminated

SR

4-19-82, negotiated agreement to reduce exposures

— —

Thiophonate methylb d 5-86 10-20-86 Label precautions —

Trlfluralin b c (contaminated

with n-nitrosamine) — Animal 8-4-82 — — Limit set for amount of —

n-nitrosamine

aThese tables Confaln only active pestlclde lrlgre~lenrs In adcjltlorl to tfle listed substances EPA has Identlfled 28 inert Ingredients of concern for polermal Carcmogemclty among 55 Iflerts Of concern fOr inherent tOxlOfY (aS of 6- I 9-85) The a9encY

IS evaluating these merts to determine the extent of use and exDosure, whether thev are essential, whether safer alternatives are avadable and what regulatory actions would be appropriate The 28 Inert Inaredlents of carcmooenlc concern are —anlllne

dlethylhexylphthala!e (DEHP), asbestos benzene, betabutyrolactone cadmtum compounds carbon Ietrachlorlde chlorobenzene chloroform 1 2.dlchloropropane dlmethyl 1 1 hydrazme 1 2 dloxane eplchlo~ohydrm ethylene d~hlorlde ethylene thlourea

formaldehyde hexachlorophene hydrazme Isophorone, methylene chlorlde 2-nltro-propane, perchloroethylene phenylphenol propylene oxide rhodamlne thlourea 1 1 I-lrmchloroelhane (methyl chloroform) tnchloroefhylene

bRegula[ed under Sec 408 FOCA Registered for food uses–tolerances estabhshed fOr pesticide uses On raW agricultural commodities

cRegulated under Delaney clause of FDCA Sec 4139(C)(3)(A) A food addltlve tolerance ,s required when the pestlclde residue level In processed food IS greater than the fOle[ance level for the raw agrlculfural commodity but may nOt be esfabllshed

for carcmogemc pesticides

dAccordlng to EPA, these compounds do not have oncogenlc effects but they have a metabollte that has shown OnCOgenlC effects [n animals

SOURCE EPA response 10 OTA request and cNed federa/ RegMer notices
1 2 5

Table 3-16.—FlFRAa

IV. Pesticides Identified as Carcinogenic But Not Reviewed or Canceled

Substance Registration standard Type of evidence Comments/other regulatory action

Acephate bc 

. . . . . . . . . . . . .

Acetochlor . . . . . . . . . . . . . .

Acifluorfen b 

. . . . . . . . . . . . .

Amdro b 

. . . . . . . . . . . . . . . . .

Asulamb

. . . . . . . . . . . . . . . . .

Azinphos methyl (Guthion)b

Chlordimeformbc . . . . . . . . .

Chlorothalonil b

. . . . . . . . . . .

Cypermethrin b 

. . . . . . . . . . .

Cyromazine (Larvadex)bc 

. .

Diclofop-methyl (Hoelon) b 

.

Dimethipine (Harvade)b

. . . .

Fenarimol . . . . . . . . . . . . . . .

Folpet b 

. . . . . . . . . . . . . . . . .

Fosetyl al (Aliette)b . . . . . . .

Glyphosate b 

. . . . . . . . . . . . .

Methanearsonic aci d

bc 

. . .

Methomyl . . . . . . . . . . . . . . .

Metolachlor b

. . . . . . . . . . . . .

Oryzalin bc 

. . . . . . . . . . . . . . .

Oxadiazon b 

. . . . . . . . . . . . . .

Paraquat bc 

. . . . . . . . . . . . . .

Parathion bc 

. . . . . . . . . . . . .

Permethrin b 

. . . . . . . . . . . . .

Terbutryn b 

. . . . . . . . . . . . . . .

Thiodicarb (Larvin)bc

. . . . . .

l-86 (pub. draft)

—

—

—

Under development

Under development

l-86 (pub. draft)

10-84

—

—

—

—

—

Under development

6-30-83

6-86

—

9-81

9-80

Pub. draft

—

4-86

Under development

—

Under development

—

Animal

—

—

—

(Potential carcinogen)

(Potential carcinogen)

Animal

Animal

—

—

—

—

—

(Potential carcinogen)

Animal

Animal

invalid study

Animal

Animal

Animal

—

Animal

(Potential carcinogen)

—

(Potential carcinogen)

—

Under review for oncogenic potential

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern

—

—

More data required; labeling requirement

EPA determined that weight of evidence for

carcinogenicity does not support regulatory action

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern and that weight of evidence for carcinogenicity does not support regulatory action

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern and that weight of evidence for

carcinogenicity does not support regulatory action

Under review for oncogenic potential

—

—

EPA determined that weight of evidence for

carcinogenicity does not support regulatory action

Manufacturing process restrictions; labeling

requirement; restricted use

—

No action taken because EPA determined that

exposure/risk from use patterns is below level for

concern

Pre-SR completed 6-29-82, returned to registration

process

—

EPA determined that weight of evidence for

carcinogenicity does not support regulatory action

Pre-SR agreement 5.12-82; label changes to reduce

applicator exposure

EPA determined that weight of evidence for

carcinogenicity does not ‘support regulatory action

aThese t~le~ contain only ~tlve pesticide ingr~~ents, In ~dition to the list~ subst~ces, EPA has identified 28 inert ingredients Of concern fOr pOtentiai CarClnOgeniClty

among 55 inerts of concern for inherent toxicity (as of 6-19-85). The agency is evaluating these iner’ls to determine the extent of use and exposure, whether they are

essential. whether safer alternatives are available. and what reauiatorv actions would be amrorxiate. The 28 inert ingredients Of carcinogenic concern are—aniline.

diethylhexylphthatate (DEHP); asbestos; benzene; betabutyroiact~ne; cao-mium compounds; carbn”tetrachlodde; chloro~nzene; chloroform; 1~2-dichloropropane; dimethyl

1,1 hydrazine 1,2; dioxane; epichlorohydrin; ethylene dichloride; ethylene thiourea; formaldehyde; hexachlorophene; hydrazine; iaophorone; methylene chloride, 2mitropropane; perchloroethylene; phenylphenol; propylene oxide; rhodamine; thiourea; 1,1 ,1-tri-chloroethsne (methyl chloroform); trichloroethylene

bRegulated under !3ec,408 FDCA. Registered for food uses —tolerances estabiiahed for pesticide uaes on raw agricultural commodities.

cRegu/ated under Delaney clause of FDCA s~. 4@fc)(3XA), A food addltlve tolerance is rec@red when the pasticide residue leVel in processed food iS greater than

the tolerance level for the raw agricultural commodity but may not be established for carcinogenic pesticides.

dAccording t. EpA, these compoundS do not have ~cogenic effects, but they have a metabolize that has shown OtlcO@flic effeCtS in animalS.

eAccordlng t. EpA, these compounds do not have oncogenic effects, but they contain a contaminant that has shown OncOgenic effeCtS in anlmalS

SOURCES: EPA response to OTA request for information, EPA correspondence with Representative Henry Waxman (10-2-85); EPA Office of Pesticide Programs, March

1988, “Report on the Status of Chemicals in the Special Review Program, Registration Standards Program, and Data Call-in Program;” GAO, April 1986,

“Pesticides-EPA’s Formidable Task to Assess to Regulate their Risks” GAO/RCED-88-l 25; EPA, “Suspended, Cancelled & Restricted Pesticides” Third

Revision, January 1985; Federa/ Register notices for each action provided information on the type of evidence used
1 2 6

Other Pending Issues

In addition to its focus on active ingredients,

EPA regards about 55 inert ingredients as “high

concern, ” with 28 of these showing carcinogenic

effects. Another 51 substances have “suspected

toxicity” while between 800 and 900 other inert

ingredients have insufficient health and safety data

(130,203). In April 1987, EPA issued a policy

statement announcing the intent to encourage the

use of the least toxic inert ingredient available,

require data necessary to determine the conditions

under which it may safely be used, and hold hearings to determine whether the use of certain inert

ingredients should continue to be permitted. EPA

also intends to reclassify some of them as active

ingredients (294).

EPA has inadequate information on a number

of nonagricultural pesticides to determine health

risks, and these pesticides have not been reassessed

by the current standards (202). After reviewing

the status of EPA’s chronic toxicity data for 50

chemicals, selected because they are used in large

quantities, the General Accounting Office found

that “EPA had done preliminary assessments for

18 of the 50 nonagricultural chemicals [pesticides

not used on crops] and found that it did not have

enough chronic toxicity data on 17 of the 18 chemicals to complete the assessments. ” A tiered approach (explained below in the section on TSCA)

in obtaining chronic test data on nonagricultural

pesticides is currently taking place through the

data call-in (21).

Finally, EPA has invalid or fraudulent health

data on 36 pesticides, including 35 food use pesticides. Some or all of these products may have

been tested by Industrial Biotest Laboratories,

which submitted invalid, and in some cases fraudulent, test data in the mid-1970s (203,206). These

data are being replaced through the data call-in

and reregistration process.

EPA REGULATORY ACTIONS UNDER TSCA

The Toxic Substances Control Act was enacted

in 1976. With TSCA Congress established the policy that chemical manufacturers are responsible

for developing data about the health and environmental effects of their chemicals, that the government regulates chemical substances that pose

unreasonable risks of injury to health or the environment, and that regulatory efforts should not

unduly impede industrial innovation. Singled out

for special concern were substances that present

or will present significant risks of cancer, gene mutations, or birth defects.

EPA actions under TSCA cover both new and

existing chemicals. For new chemicals, the principal focus is a premanufacturing review. After

review of available information, EPA can request

or require additional toxicity testing, can require

certain workplace practices and controls, and can

require that the manufacturer notify EPA before

putting the chemical to a “significant new use.”

For existing chemicals, EPA can require testing

for toxicity and environmental effects, designate

the chemical for priority review, require that “significant new uses” be reported, require manufacturers, importers, and processors to report production and use information, or require that they

submit copies and lists of unpublished health and

safety studies to EPA. EPA can also issue regulations restricting or banning the production of a

chemical or limiting its uses.

New Chemicals

Under section 5 of TSCA, chemical manufacturers must submit a premanufacturing notice

(PMN) for any “new chemical.” “New chemicals”

are those not found in the TSCA inventory of

chemicals in commerce. At the end of EPA’s review, any one of four actions are possible:

1. The substance described in the PMN can be

manufactured without restriction.

2. The substance can be manufactured for the

uses described in the PMN, but the Agency

can require that it be notified if manufacture

for a significant new use is considered. If

EPA decides that a potential new use of the

substance might be associated with an unreasonable health or environmental risk, it
1 2 7

3.

4.

can by a separate rulemaking procedure issue a Significant New Use Rule (SNUR) to

restrict the manufacture or distribution of the

substance (section 5(a)(2)).

The manufacture, processing, distribution,

use or disposal of the new substance can be

regulated pending the development of additional information about the substance (section 5(e)).

The manufacture, processing, distribution,

use, or disposal of the new substance can be

regulated because it presents or will present

an unreasonable risk (section 5(f)) (222).

From July 1979, when the program started, until September 1986, EPA received 7,356 valid

PMNs (see table 3-17). EPA decided that no further action was necessary for 5,761 of these, or

about 80 percent. Of the remaining chemicals that

raised EPA concerns, 523 were subject to some

kind of action. EPA concerns led to the manufacturers’ agreeing to voluntary testing in 64 cases,

voluntary control actions such as the use of personal protective equipment in 33 cases, and the

complete withdrawal of the PMN in 139 cases.

Thus, in 236 cases or about 45 percent, the threat

of EPA action lead to informal, “voluntary” responses by the manufacturers. The other half of

the time the actions were more formal: 271 chemicals subject to consent orders under which the

manufacturers agree to controls for worker exposure, or restrictions on production use or disposal

until testing is done (section 5(e)); 12 unilateral

orders under which EPA imposes restrictions or

bans pending until testing is completed (section

5(e)); and 4 chemicals subject to immediately effective proposed rules setting permanent requirements for the production of these chemicals (sections 5(f) and 6(a)). EPA has received notices of

commencement of manufacture for 3,678 of the

7,356 chemicals.

In 1983, OTA prepared a background paper,

The Information Content of Premanufacture Notices, describing the nature and extent of information reported on PMNs submitted during a

2-year period from 1979 to 1981, and on PMNs

submitted for June of 1982. That study found that

about half the submitted PMNs reported no toxicity information and “only 17 percent of PMNs

have any test information about the likelihood of

Table 3-17. -TSCA: New Chemicals,

Section 5 PMN Reviews

Total

(1979-86)

Valid PMNs received . . . . . . . . . . . . . . . . . . . 7,356

PMNs requiring no further action. . . . . . . . . 5,761

Some action . . . . . . . . . . . . . . . . . . . . . . . . . . . 523

Voluntary testing. . . . . . . . . . . . . . . . . . . . . . . 64

Voluntary control actions . . . . . . . . . . . . . . . 33

PMNs voluntarily withdrawn . . . . . . . . . . . . . 139

Section 5(e) consent orders. . . . . . . . . . . . . . 271

Unilateral 5(e) orders. . . . . . . . . . . . . . . . . . . . 12

Section 5(f) rules . . . . . . . . . . . . . . . . . . . . . . . 4

New chemicals subject to SNUR:

Proposed. . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Final . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

SOURCE: EPA response to OTA request for information

the substance’s causing cancer, birth defects or

mutations—three biological effects that were singled out for special concern in TSCA” (222). Because long-term experiments in whole animals are

expensive, the tests conducted for all these PMNs

were short-term mutagenicity tests.

The submitters of nine of the PMNs examined

by OTA did not begin manufacture because of

EPA actions. Six of the substances were phthalates, of special concern because of a recent National Cancer Institute study showing some phthalates to be carcinogenic (222). Two of the

remaining three were benzidine dyes, which have

long been associated with human carcinogenicity. The submission of these PMNs shows that

substances of demonstrated toxicity, even substances closely related to known carcinogens, are

still considered for possible manufacture and use.

Because most PMNs do not contain any toxicity test information, EPA is forced to rely on

structure-activity relationships in attempting to

predict, from the chemical structure of the substance, the hazards it poses. In this case, EPA uses

computerized databases on chemical structures to

identify related chemicals or analogs. EPA then

searches toxicity databases for information on the

analogs. EPA staff admit that the identification

of analogs is a “rather subjective process, ” and

that the final assessments concerning a new chemical rely on the “knowledge and professional

judgments” of the staff performing the evaluation

(11).
1 2 8

Existing Chemicals—Obtaining

Additional Data

Section 4(e) of TSCA created an Interagency

Testing Committee (ITC) to review existing chemicals and make recommendations to EPA about

testing chemicals for health and environmental effects. EPA is to review these recommendations

and then decide whether testing should or should

not be required. TSCA provides that ITC shall

give “priority attention” to chemicals that cause

or are suspected of causing cancer, mutations, or

birth defects. ITC can simply commend a substance or mixture to EPA’s attention, or ITC can

“designate” it, in which case EPA has 12 months

to initiate a proceeding to require testing or publish reasons for deciding that testing is unnecessary.

The recommendations are in the form of a list

of chemical substances and mixtures. This “Priority List” of “designated” chemicals awaiting EPA

action at any one time cannot exceed SO.

By statute, ITC consists of representatives from

EPA, OSHA, NIOSH, the National Institute of

Environmental Health Sciences, the National Cancer Institute, the National Science Foundation, the

Council on Environmental Quality, and the Department of Commerce. In addition, seven other

agencies belong to ITC as “liaison members”:

CPSC, FDA, NTP, the U.S. Department of Agriculture, the U.S. Department of Defense, the U.S.

Department of the Interior, and the National Library of Medicine. They participate in the reviews

of chemicals and the meetings of ITC, although

they do not vote to select the chair of ITC or on

the contents of the final reports.

TSCA specifies a number of factors for ITC to

consider in designating substances and mixtures:

●

●

●

●

●

the quantity that is or will be manufactured,

the quantity that enters or will enter the environment,

the extent of occupational exposures (both

numbers of workers and durations of exposure),

the number of people exposed (presumably

including people exposed outside the workplace),

the similarity to other substances known to

●

●

●

present unreasonable risks to health or the

environment,

the existence of data on health and environmental effects,

the extent to which testing may result in data

useful for predicting effects on health or the

environment, and

the availability of testing facilities and personnel (sec. 4 (e)).

Using a periodic process called a “scoring exercise, ” ITC narrows down the universe of chemicals in commerce (over 50,000) in several steps

to select a manageable number (40-so) for detailed

review by ITC members. The most recent scoring

exercise—the sixth, completed in January 1987—

began with a list of approximately 20,000 organic

chemicals. The first step was to remove chemicals previously reviewed by ITC, as well as common metabolizes, chemicals “generally recognized

as safe (GRAS), ” food additives, drugs, pesticides,

certain regulated chemicals, and widely occurring

natural products. The remaining chemicals on the

master list were then arrayed in different lists

based on potential health effects, potential ecological effects, presence in the environment, potential high workplace exposures, and potential

high consumer exposure. Each chemical then received a “score” based on the frequency of occurrence on these lists. Chemicals not produced or

imported in significant quantities were removed,

and the remaining substances were scored for exposure potential, health effects, and ecological effects. From these scores, chemicals were selected

for more detailed review by ITC. More detailed

information was prepared for these chemicals, and

then ITC made its recommendations to EPA (335).

A major problem in this process is the difficulty

of obtaining current data on the volumes of domestic production and imports (16).

ITC transmits an updated list of recommended

substances to EPA at least every 6 months. These

reports are published in the Federal Register for

public comment. The first ITC report was published in October 1977; report number 19 came

out in November 1986.

EPA’s responses to the ITC lists have generated

concern, both for the length of time they have

taken to develop responses and for the procedures
1 2 9

chosen for obtaining the necessary test data. During the first years of the program, from the first

ITC report in 1977 until the sixth in November

1980, EPA never responded within the statutory

deadline of 12 months. Because of this failure to

act, NRDC sued EPA. In a decision in early 1980,

a New York District Court ruled that EPA had

failed to fulfill its responsibilities to act on ITCdesignated chemicals. As a result, for reports 7

through 16, EPA has responded within the deadline for all designated chemicals (195).

At the time of the initial lawsuit, EPA also developed a new procedure to negotiate agreements

with chemical manufacturers concerning the conduct of toxicity tests. These negotiated testing

agreements were designed to avoid what EPA

viewed as the difficulties of the rulemaking procedures mandated by TSCA. Six hundred studies

were produced under 22 of these agreements (341).

In 1983, EPA was sued a second time by

NRDC, on the grounds that TSCA did not provide for these voluntary negotiated testing agreements and that such agreements did not trigger

certain other provisions of the law. The court

agreed and ordered EPA to reconsider its decisions

on several chemicals. In 1985, NRDC and the

Chemical Manufacturers Association (CMA) approached EPA concerning these issues. The result

was a new set of EPA procedures under which

EPA attempts to negotiate a consensus among all

interested parties on testing needs. If negotiation

fails, EPA will develop a test rule. In either case,

EPA appears committed to the prompt resolution

of these issues, i.e. meeting the statutory deadline (338).

In 1985, ITC created a “recommended with

intent-to-designate” category for chemicals it intends to designate in the future. This new category enables EPA to begin gathering production

and use data, and information on unpublished

health and safety studies (see discussion below),

before the statutory l-year clock starts ticking.

EPA regards this category as essential for using

the negotiated consent agreement process since negotiations require an additional 10 weeks (341).

Any information obtained in this way can also

be reviewed by ITC before making the final decision to “designate” the chemical.

Counting the total number of chemicals recommended by ITC and considered by EPA is difficult, because a single recommendation may cover

a single chemical or a group of chemicals. In the

19 reports published through September 1986,

ITC has recommended testing for 101 chemicals

or groups of chemicals. Of these, 94 were “designated. ”15 Counting all of the discrete chemicals

in the various groups of chemicals under consideration yields a total of 389 chemicals (17,18).

In all, EPA has issued 20 final rules on testing

for various health and environmental effects (not

necessarily carcinogenicity). Another 24 proposals

for test rules are pending, and 5 chemicals or

chemical groups have been the subjects of ANPRMs.

Finally, for 51 chemicals or chemical groups, EPA

has decided that testing is not needed (“decisions

not to test”), and for 1 category, EPA returned

the category to ITC (195).

Table 3-18 presents the 17 chemicals from the

ITC reports for which EPA has required, proposed, or negotiated carcinogenicity testing. These

include 11 chemicals to be tested in carcinogenicity

bioassays and 6 tested in “tiered testing, ” which

involves conducting a battery of short-term tests

and then evaluating the results before deciding

whether to require a long-term bioassay.

EPA can require testing under section 4 for

chemicals in addition to the ones recommended

by ITC, but this has been less frequent than consideration of ITC-recommended chemicals. Recent

proposals concerning 1,1-dichloroethylene, diethylene glycolbutyl ether, 2-ethylhexanol, and

a group of 73 substances found at hazardous waste

sites are the exceptions. The latter two were nominated by other program offices at EPA, the Air

Office and the Office of Solid Waste and Emergency Response, respectively. This may mark the

beginning of a new trend, but thus far the testing

agenda under TSCA has been set by ITC and its

recommendations. According to EPA this is because, under section 4(e), ITC designations have

top priority, and, also because of resource limitations (341).

15In the 19th report, two additional chemicals were recommended

with “intent-to-designate. ” The 94 “designated” chemicals include

three that had been similarly recommended with “intent-to-designate”

in reports 17 and 18.
130

Table 3-18.—TSCA: Existing Chemicals;

Testing Required To Determine Carcinogenicity

ITC nomination Negotiated

date of Federal testing

Name publication agreement NPR Final Type’

Alkyl phthalates . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzyl butyl phthalate . . . . . . . . . . . . . . . . . . . .

Antimony trioxide . . . . . . . . . . . . . . . . . . . . . . . .

Aryl phosphates. . . . . . . . . . . . . . . . . . . . . . . . . .

2-(Butoxyethyl) ethyl acetate . . . . . . . . . . . . . . .

Chlorinated benzene . . . . . . . . . . . . . . . . . . . . .

4-Chlorobenzotrifluoride . . . . . . . . . . . . . . . . . . .

2-Chlorotoluene . . . . . . . . . . . . . . . . . . . . . . . . . .

Cresols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cumeme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diethylene thiamine.. . . . . . . . . . . . . . . . . . . . . .

Ethyl toluenes . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fluoroalkenes. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Glycidol & derivatives . . . . . . . . . . . . . . . . . . . . .

Mesityl oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oleylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenylenediamines . . . . . . . . . . . . . . . . . . . . . . .

10-12-77

11-25-80

6-1-79

4-19-78

12-14-83

10-12-77

2-5-82

5-22-81

10-12-77

11-29-84

5-22-81

5-25-82

11-25-80

10-30-78

6-1-79

12-14-83

5-28-80

1-5-82

1-5-82

9-2-83 —

—

7-18-83

4-28-82

—

—

—

6-4-84

—

—

—

—

a

9-6-85

c

12-19-83 (ANPR)

8-4-86

1-13-84

d

d

7-11-83

11-6-85

4-29-82

5-23-83

11-6-85

12-30-83 (ANPR)

7-5-83

11-19-84

1-6-86

— c

Pendingb

c

— c

T

Pending c

7-8-86 c

— T

— T

4-28-86

Pending c

5-23-85 c

5-17-85 T

Pending c

c

12-20-85 T

Pending

Pending** C

● Type C = carcinogenicity testing in 2-year bioassays; type T = tiered testing.

● *Decision not to test certain phenylenediamines. Others still under review.

aphase I negotiated Testing Program compieted. Data under review to determine further te!Nin9 needs.

bAdequate environmental data submitted. Health testing needs under review. See fOOtnOtea.

clndust~ currentl y Pefloming carcinogenicity bioassay under Negotiated Testing Agreement.

aData adequate. Carcinogenicity te9tin9 nOt tdggered.

SOURCE: EPA response toOTA request for information.

EPA may issue rules, under section 8(a), to require manufacturers, importers, and processors

to provide information on production and uses

of a chemical, plant characteristics, process characteristics, environmental releases, and worker exposures. Rules adopted under section 8(d) require

that manufacturers, importers, and processors

submit to EPA copies and lists of unpublished

health and safety studies. (This is different from

the general obligation under section 8(e) to notify

EPA of studies revealing any “substantial risks.”

A section 8(d) rule requires the submission of all

studies: positive and negative, “substantial risks”

or not. )

Again, ITC recommendations have dominated

EPA activity under these sections of TSCA. EPA

has issued 8(a) and 8(d) rules for all the substances

recommended by ITC, and in fact now routinely

adds the chemicals from each new ITC report to

the 8(a) and 8(d) lists within a few days after receipt of the report (108). Until 1986 there had been

relatively few chemicals included under 8(a) and

8(d) that were not included in ITC reports. This

may now be changing. For example, in the past

year, 33 chemicals nominated by the Office of

Solid Waste were added to the 8(d) list (320), and

in May 1987 EPA published a final rule under section 8(d) that listed 107 chemicals nominated by

the Offices of Toxic Substances, Water, and Solid

Waste within EPA as well as by the CPSC (344).

For section 8(a) rules in general, EPA has proposed a Comprehensive Assessment Information

Rule, to establish uniform reporting requirements

for chemicals that are subject to 8(a) rules. The

proposal includes a list of 47 chemicals nominated

by EPA’s Air Office and Office of Toxic Substances, CPSC, OSHA, and NIOSH (308).

Under section 8(e) of TSCA, manufacturers,

processors, and distributors of chemicals are required to notify EPA of information supporting

the conclusion that a chemical “presents a substantial risk of injury to health or the environmerit. ” Since January 1977 when this requirement

became effective, EPA has received over 600 such

notifications. In addition, EPA also receives “for

your information (FYI)” notifications which do

not fit the statutory requirements of section 8(e).

The section 8(e) and FYI notifications are evaluated and EPA staff identify which chemicals

should receive further attention, such as the prep-
131

aration of Chemical Hazard Information Profiles

(CHIPS). The information provided in the 8(e) notices is made available to the interested public and

is reported through the use of bulletins, published

chemical status reports, and a computer database

(341). Finally, EPA promulgated an 8(a) rule to

update the information in the TSCA inventory

of chemicals in commerce by requiring manufacturers and importers to report current data on production volume and plant site. The data in the

original inventory was reported in 1977 and is out

of date. Under the new rule the data must be reported every 4 years (335).

The various reporting requirements of TSCA

have undoubtedly stimulated increased awareness

in the chemical industry. Companies must evaluate information they obtain to determine whether

it meets the notification requirements. Even if it

does not, the information may be reported to

EPA. To some extent, companies will voluntarily reduce exposures, conduct additional studies,

change product labels and Material Safety Data

Sheets (which provide information on product

hazards and safe handling), and notify exposed

workers, consumers, or others (341).

Existing Chemicals—

Identified Hazards

For some existing chemicals, there may be

enough information to determine that they cause

cancer. For these chemicals, the issues are determining whether this risk of cancer is “unreasonable” and whether actions are needed to reduce or

eliminate these risks. Table 3-19 lists 40 substances

or groups of substances that EPA’s Office of Toxic

Substances has identified as carcinogenic, based

on information provided to OTA. EPA has prepared hazard analyses and/or risk assessments for

25 of those substances.

This list does not cover all the substances for

which TSCA evaluations, such as CHIPS, have

been prepared. A CHIP provides a concise summary of available information on a chemical, including physical and chemical properties, estimates of exposure and environmental fate, health

effects, environmental effects, and existing standards and recommendations. As of March 1987,

CHIPS have been prepared for 93 different chemicals with carcinogenic concerns (336). CHIPS are

initiated when EPA receives information on potential hazard from NTP bioassays, published scientific papers, or submissions to EPA under section 8(e). Using the information in a CHIP, EPA’s

Office of Toxic Substances may decide to develop

more information on exposures, refer the chemical to other agencies or EPA programs, or begin

action under TSCA.

EPA provided OTA with limited information

about the kinds of evidence used for these identifications and risk assessments; most have relied

on animal data. From the list in table 3-19, only

asbestos and certain aromatic amines are known

to be carcinogenic from human studies. The remainder are based on animal data, including 15

tested in NCI/NTP bioassays.

Regulatory actions for this group of existing

chemicals consist of 4 designations under section

4(f) for an expedited review (4,4’-methylene dianiline, 1,3-butadiene, formaldehyde, and methylene chloride), 10 proposed or final SNURs for

existing chemicals, and proposed section 6 regulatory actions for 4 substances.

The first section 4(f) designation, for 4,4’-

methylene dianiline, occurred in 1983. Formaldehyde, designated in May 1984, had been considered in 1982 for designation. John Todhunter, the

first director of the Office of Pesticides and Toxic

Substances in the Reagan Administration, however, decided against designation—a controversial decision at the time. Following a lawsuit by

NRDC, EPA formally acknowledged that section

4(f) applied to formaldehyde and announced a

regulatory investigation in an ANPRM (158).

EPA response to its evaluation of chemicals under section 4(f) has been to refer chemical exposures limited to the workplace to OSHA under

a provision of TSCA (sec. 9) that provides for

referrals if EPA believes that OSHA, may be able

to address the hazard. This has happened for acetaldehyde, acrylamide, chloromethane, 4,4-methylene bis (2-chloroaniline), toluenediamine, 4,4’-

MDA, 1,3-butadiene, and for the occupational exposures associated with formaldehyde (see table

3-19). EPA is still investigating risks associated

with nonoccupational exposure to formaldehyde

in pressed wood products. The section 4(f) find-
1 3 2

Table 3-19.—TSCA: Existing Chemicals Identified as Carcinogens

Hazard/risk

Name assessment Action

Acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acrylamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

II-Aminoundecanoic acid . . . . . . . . . . . . . . . . . . . . . . . .

Aniline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Aromatic amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,3-Butadiene a

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clarified slurry oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorinated paraffinsa 

. . . . . . . . . . . . . . . . . . . . . . . . . . .

Chloromethane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-Chloro-2-methylpropene (CMP)a 

. . . . . . . . . . . . . . . . .

C.I Disperse Yellow 3a . . . . . . . . . . . . . . . . . . . . . . . . . .

D&C Red 9a 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,4-Dichloro-2-butene (DCB) . . . . . . . . . . . . . . . . . . . . . .

1,4-Dichiorobenzene a 

. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dihydro safrole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethanolamines & metalworking fluids. . . . . . . . . . . . .

Etheylenediaminetetra methylenephosphonic acid . .

Formaldehyde. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Glycol ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorobenzene (HCB) . . . . . . . . . . . . . . . . . . . . . . .

Hexachloronorbornadiene (HexBCH) . . . . . . . . . . . . . .

Hexafluoropropylene oxide . . . . . . . . . . . . . . . . . . . . . . .

Hexamethyl phosphoramide (HMPA) . . . . . . . . . . . . . .

4,4-Methylenebis (2-chloroaniline) . . . . . . . . . . . . . . . . .

Methylene chloridea

. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4,4’-Methylenedianiline a 

. . . . . . . . . . . . . . . . . . . . . . . . .

Naptha solvent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-Nitropropane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Paradichlorobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Pentachloroethane (PCE)a 

. . . . . . . . . . . . . . . . . . . . . . . .

Perchloroethylene (perc)a 

. . . . . . . . . . . . . . . . . . . . . . . .

Phthalates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DEHPa 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Polychlorinated biphenylsb 

. . . . . . . . . . . . . . . . . . . . . . .

Propylene oxidea 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Toluenediamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Urethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vinvlcyclohexene a 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Section 9 referral to OSHA

Section 9 referral to OSHA; section 6 designation

SNUR for new acrylates under consideration

SNUR issued

ANPR for testing

Section 6: rules on asbestos removal: proposed ban/

phase-down

Section 4(f) designation; section 9 referral to OSHA

Section 9 referral to OSHA

EPA has taken no action because

systems

Proposed SNUR

use is in closed

Advisory warnings; section 6 proposal

Section 4(f) designation; termination of investigation

§ion 9 referral to OSHA for occupational

exposures

Section 9 referral to OSHA

SNUR & 8(a) rules issued

SNlJR & 8(a) rules issued

Proposed SNUR

SNUR issued

SNUR proposed, section 8(a) rule issued. Section 9

referral to OSHA

Section 4(f) designation

Section 4(f) designation; section 9 referral to OSHA

Advisory warning

SNUR issued; 8(d) rule

Decision not to designate under 4(f)

Section 6 rules

EPA’s quantitative risk assessment indicates risk is

low

Advisory warning, section 9 referral to OSHA

SNUR issued

~estedby NC1/NTP,

b Not in “parf2%mmarY,” but regulated byEPA under TSCA.

SOURCE: EPA,OTS, “Part 2: Summary Narratives of Chemical Dispositions, “in EPA response to OTA request for information on substances identified as carcinogenic

ing for methylene chloride initiated an interagency under the terms of the SNUR. If EPA receivessuch

regulatory investigation of hazards associated notice, it can take action under section 5(e) or 5(f)

with methylene chloride and five other chlorinated to impose controls or prohibit production.

solvents. All four designations under section 4(f) SNURs can be based on concern for any of the are based on results of animal studies. health and environmental effects regulated under

After EPA issues a SNUR, a manufacturer must TSCA, including carcinogenicity. Table 3-21 lists

notify EPA before beginning production that falls the existing chemicals for which carcinogenicity
1 3 3

Table 3-20. -TSCA: 4(f) Reviews

4(f) Notice of ANPR summarizing

accelerated review evidence Final action

4,4’ -Methylene dianiline . . . . . . 4/27/83 9/20/83 7/5/85—Section 9(a) referral to

1,3-Butadiene. .

Formaldehyde .

Methylene chlori

OSHA

. . . . . . . . . . . . 1/5/84 5/15/84 10/10/85—Section 9(a) referral to

OSHA

. . . . . . . . . . . . 11/18/83 5123184 3/19/86—Announced termination

of investigation concerning

occupational exposures; nonoccupational exposures still

being investigated

de. . . . . . . . . . 5/14/85 10/1 7/85 Pendina

SOURCE: EPA response to OTA request for information

was one reason for the SNURs. The table shows

that for existing chemicals considered to be carcinogenic, EPA began proposing SNURs in 1984,

nearly 7 years after enactment of TSCA.16 The

table shows that EPA has proposed six SNURs

(for eight chemicals) and issued four final SNURs

on chemical substances of carcinogenic concern.

For Hex-BCH it also issued a section 8(a) rule requiring reporting of production volumes. EPA issued an 8(a) rule for MBOCA instead of an SNUR.

(See table 3-21. )

Section 6 provides wide-ranging authority to

limit production and uses, which includes banning substances. Table 3-22 presents EPA actions

concerning carcinogens under this section. Congress prohibited the manufacture of PCBs in the

act itself, and required that EPA issue rules concerning their use and disposal.

EPA also issued rules in 1982 concerning identification and notification of asbestos in school

buildings. In 1987, EPA proposed to require removal of this asbestos in certain circumstances.

EPA has also issued rules to regulate the exposures

of asbestos-removal workers who are not covered

by OSHA standards. In 1986, EPA issued a proposal concerning asbestos, including proposed

bans of certain asbestos applications (for which

EPA has concluded there are available substitutes)

and to “phase down, ” over 10 years the amount

of asbestos that may be mined or imported. That

proposal has not been issued in final form.

16The total number of SNURS issued for carcinogenic and other

concerns is 9 proposed (for 11 chemicals) and 8 final.

One other group of substances—chlorofluorocarbons (CFCs)—have been acted on under section 6. EPA banned use of CFCS as aerosol propellants and in 1980 issued an ANPRM concerning

a possible limit on production and consumption

of these substances for other uses, which may

harm the ozone layer. That harm might have large

consequences on the earth’s climate, as well as increasing the amount of ultraviolet radiation reaching the earth’s surface. Increased ultraviolet exposure would lead to an increase in the rate of

skin cancer; thus CFCs in the atmosphere might,

indirectly, be considered carcinogens. If further

regulations or control of CFCs are proposed, such

actions will not be proposed under TSCA, but

rather, under section 157(b) of the CAA (47).

Another section 6 action that has not been issued in final form is a 1984 proposal concerning

certain potentially carcinogenic compounds that

may form in metalworking fluids.

Table 3.21 .—TSCA: Existing Chemicals,

Significant New Use Rules for Carcinogens

Name Proposed Final

Epichlorohydrin . . . . . . . . . . . . . . . 1-2-87 —

Hexachloronorbornadiene

(HEX-BCH) . . . . . . . . . . . . . . . . . . 2-22-85 1 l-19-85a

Hexafluoropropylene oxide . . . . . 1-2-87 —

Hexa methylphosphoramide

(HMPA) . . . . . . . . . . . . . . . . . . . . . 10-10-84 3-19-86

4,4’ -Methylenebis

(2-chloroamiline) . . . . . . . . . . . . . 4-26-85 4-18-86b

Pentachloroethane. . . . . . . . . . . . . 3.24-86 9-9-&36

Trichlorobutylene oxide . . . . . . . . 1-2-87 —

Urethane . . . . . . . . . . . . . . . . . . . . . 10-10-84 3-19-86

aSNuR and section 8(a) rule.

b

issued as section t3(a) rule.

SOURCE: EPA response to OTA request for information.
134

Table 3-22.—TSCA: Existing Chemicals;

Section 6 Actions

Substance Regulation ANPRM NPRM Final

Asbestos . . . . . . . . . . . . . . . . . .Statement of policy on coordination of

regulatory activities

Asbestos . . . . . . . . . . . . . . . . . . Asbestos in schools: identification and

notification

Asbestos . . . . . . . . . . . . . . . . . . Asbestos abatement projects/worker

protection

Asbestos . . . . . . . . . . . . . . . . . . Mining and import restrictions and

manufacturing; importation and processing

prohibitions (asbestos ban & phase out)

CFCS* . . . . . . . . . . . . . . . . . . . . . Prohibition of several uses

CFCS* . . . . . . . . . . . . . . . . . . . . . Production restriction

Metalworking fluids . . . . . . . . . Prohibition of nitrites in

PCBS. . . . . . . . . . . . . . . . . . . . . . Ban rule

PCBS . . . . . . . . . . . . . . . . . . . . . . Exclusions, exemptions, and use

authorizations for PCBs under 50 ppm

PCBs . . . . . . . . . . . . . . . . . . . . . . Electrical equipment

PCBs . . . . . . . . . . . . . . . . . . . . . . Use in closed and controlled waste

manufacturing processes

PCBs . . . . . . . . . . . . . . . . . . . . . .Amendment to use authorization for PCB

railroad transformers

PCBs . . . . . . . . . . . . . . . . . . . . . .Approval for PCB disposal facilities

(procedural amendment)

PCBs . . . . . . . . . . . . . . . . . . . . . . Use in microscopy and R&D proposed rule

PCBs . . . . . . . . . . . . . . . . . . . . . . Manufacture, processing, distribution in

commerce exemptions

PCBs . . . . . . . . . . . . . . . . . . . . . . Policy for compliance and enforcement of

PCB storage for disposal regulation

10-17-79

9-17-80

7-12-85

1-29-86

5-13-77

10-7-80

1-23-84

12-8-83

4-22-82

6-8-82

11-18-81

3-30-83

11-17-83

11-1-83

11-17-83

5-27-82

4-25-86

2-25-87

(revised final)

3-17-78

pending

5-31-79

7-10-84

8-25-82

10-21-82

1-3-83

3-30-83

7-10-84

7-10-84

11-17-83

● Not a carcinogen, but possible effects of CFCs on atmospheric ozone might increase skin cancer rates.

SOURCE: EPA response to OTA request for information.

EPA REGULATORY ACTIONS UNDER RCRA

The Resource Conservation and Recovery Act

of 1976 was enacted to protect health and the environment from chemical wastes and to conserve

material resources. Subtitle C of RCRA establishes

a hazardous waste management system. EPA has

issued regulations on the identification and listing of hazardous wastes, established recordkeeping and reporting requirements for generators,

transporters, storers, and disposers of hazardous

wastes, and permit requirements for treatment,

storage, and disposal of hazardous waste. EPA

requirements also establish a manifest system for

tracking the movement of wastes from generation

to disposal.

Wastes are subject to regulation under RCRA

if they have the characteristics of hazardous

waste, if they are listed as hazardous wastes, or

if they are mixtures containing listed hazardous

wastes. EPA did not include carcinogenicity and

other acutely toxic effects among the characteristics of a hazardous waste, but instead regulates

these substances through the listing mechanism.

According to EPA, the test protocols for such

characteristics are either insufficiently developed

or too complex and dependent on the use of highly

skilled personnel and specialized equipment to

place the burden on generators of the waste (288).

Among the characteristics, however, is “Extraction Procedure (EP) Toxicity.” This provision

specifies the maximum amount of 14 particular

contaminants that may be found in a waste using

a specific detection method. Most of the 14 contaminants are carcinogens.

A solid waste may be listed as a hazardous

waste if it exhibits the characteristics of hazardous waste, if it is acutely hazardous, or if it contains toxic constituents listed in 40 CFR Appendix VIII. Carcinogenicity is one of the criteria for
1 3 5

listing a chemical in Appendix VIII (107,221). In

May 1980, EPA published three generic lists of

wastes considered to be hazardous and subject to

the RCRA Subtitle C hazardous waste management regulations (40 CFR 261.31-40 CFR 261.33).

EPA’s lists contain 361 commercial chemicals

and 85 industrial waste processes, with others proposed as additions (not including Appendix VIII).

Where possible, EPA emphasized waste streams

from commercial processes, rather than specific

hazardous substances to relieve waste generators

of testing burdens and uncertainties in “relating

a waste containing many substances to a list of

specific substances” (290). Appendix VIII includes

391 constituents of the listed commercial compounds; many of them are carcinogens. The distinction between carcinogenicity and acute toxicity or other chronic health effects was not of

particular concern to EPA when the list was compiled, since all of these criteria were used as the

basis for the Appendix VIII listing.

Any listed waste is subject to RCRA “proper

handling” regulations unless it is “delisted.” Delisting a substance requires a petition for a regulatory amendment and is subject to requirements

for public notice and comment. Although the Appendix VIII list of hazardous constituents is nonregulatory, inclusion of a substance on it may provide the basis for listing a commercial chemical

product on the regulatory list. Waste generators

may also be required to monitor groundwater for

the constituents as a condition of their permits.

RCRA was passed in 1976. Congress gave EPA

18 months from the date of passage to provide

criteria for characteristics of hazardous wastes and

to list hazardous wastes. EPA issued its proposed

rules on these topics in December 1978. In May

1980, it issued its first final rule concerning lists

and characteristics of hazardous wastes (some

other regulations are to follow). Also in 1980,

EPA issued final rules for “proper handling” of

hazardous wastes.

EPA has had considerable difficulty in adding

to the list of hazardous wastes. Since issuing its

list of 361 commercial chemicals and 85 industrial

waste processes as well as the 4 generic waste characteristics in 1980, EPA has added 5 additional

wastes, and no new characteristics. Moreover,

EPA does not know whether the existing lists

cover 90 percent of potentially hazardous wastes

or 10 percent. Some of the as yet unlisted wastes

are highly toxic, such as certain pesticides and

known carcinogens (200).

Congress, in the 1984 RCRA amendments, addressed a number of aspects of the solid waste program. Relevant to this discussion of regulating

chemicals for carcinogenicity were a series of congressional deadlines for EPA action and automatic

bans on land disposal (known as “hammers”) for

particular, specified wastes if EPA fails to act by

the deadlines for issuing treatment standards. The

1984 amendments also required that EPA review

its waste list in three stages (ending in 1990) and

decide whether to ban land disposal of these

wastes (334).

EPA REGULATORY ACTIONS UNDER CERCLA

While RCRA was prospective—designed to prevent problems from hazardous wastes in the

future—the Comprehensive Environmental Response, Compensation, and Liability Act of 1980,

also known as “Superfund,” was designed to address the cleanup of inactive hazardous waste

sites, manage emergency response to the release

of hazardous substances into the environment,

and provide for liability and compensation.

CERCLA addresses problems ranging from spills

requiring immediate responses, to hazardous

waste dumps leaking into the environment and

posing long-term health and environmental

hazards.

The list of hazardous substances is established

under section 101(14) of CERCLA. Section 102

of CERCLA authorizes EPA to list additional hazardous substances—those substances which,

“when released into the environment may present

substantial danger to the public health or welfare

or the environment. ” Also, EPA is to set “report-
1 3 6

able quantities” (RQs) for all of these substances.

The RQs are set by statute at 1 pound except when

different reportable quantities have been set under section 311(b)(4) of the Clean Water Act. EPA

is authorized to adjust RQs by regulation (42

U.S.C. 9602). Section 103 sets requirements

notifying appropriate government officials in the

event that a hazardous substance is released in

amounts greater than the relevant RQ.

“Hazardous substances” under section 101(14)

of CERCLA include substances specified by sections 307 and 311 of the Clean Water Act, section 3001 of the Resource Conservation and Recovery Act, section 112 of the Clean Air Act, and

section 7 of the Toxic Substances Control Act,

and any substance designated as hazardous under

section 102 of CERCLA (42 U.S.C. 9602). Of the

CERCLA hazardous substances, 191 were identified as “potential carcinogens” (table 3-23).17

In 1985, EPA issued a final rule that clarified

reporting procedures and set final RQ adjustments

for 340 substances from its list of 717 hazardous

substances (307). In 1986, EPA finalized RQ adjustments for an additional 102 hazardous substances (316). These adjustments did not cover potential carcinogens. In March 1987, EPA proposed

RQ adjustments for the 191 substances identified

as potential carcinogens on the CERCLA list (314).

To identify potential carcinogens on that list,

EPA used IARC monographs, the Annual Report

on Carcinogens (see ch. 5), final EPA determinations on carcinogenicity for other regulatory programs, and determinations by EPA’s Carcinogen

Assessment Group. EPA then developed a hazard

ranking for the CERCLA substances that appeared

on these various lists of carcinogens. The hazard

ranking is a method used to sort a list of potential carcinogens into levels of relative carcinogenicity, which may then be equated to RQ levels

for notification purposes (314).

The hazard ranking consisted of both qualitative and quantitative evaluations. For the qualitative portion, the chemicals were grouped using

the CAG weight-of-evidence classification scheme

17The carcinogens on the CERCLA list were identified in a technical background document prepared by Environmental Monitoring Services Inc. (56) in support of the proposed rule to adjust the

reportable quantities for carcinogens issued in March 1987 (314).

(see ch. 2 and below). For the quantitative assessment, a potency factor was estimated by EPA’s

Carcinogen Assessment Group. For this hazard

ranking, each potential carcinogen was placed in

one of three potency groups, based on the estimated dose required to induce cancer in 10 percent of a population exposed for 70 years. In the

final step in the ranking, the qualitative weightof-evidence and quantitative potency grouping are

combined to yield a relative hazard ranking—

high, medium, or low—for each chemical.

For this ranking, 191 chemicals were placed in

the weight-of-evidence categories. Fourteen chemicals were placed in group A (sufficient human

evidence), 8 in group B1 (limited human evidence,

sufficient animal evidence), 102 in group B2 (sufficient animal evidence only), 20 in group C (limited

animal evidence only), and 7 in group D (no evidence for carcinogenicity). Two more chemicals

were given a range: one in groups B1 and B2, and

one in groups B2 and C. Finally, for 37 chemicals, there were no data for directly determining

their carcinogenicity, but these chemicals were either compounds of known carcinogenic metals

(for example, compounds of arsenic, beryllium,

cadmium, chromium, and nickel) or members of

chemical families of known carcinogens (for example, PCBs) (56). Thus, most of the chemicals

were classified based on animal evidence.

The final grouping, after combining weight-ofevidence and potency estimates, had 62 chemicals in the “high,” 77 in the “medium,” and 45 in

the “low” hazard groups; 7 chemicals were not

ranked because of lack of evidence for carcinogenicity.

CERCLA was enacted in 1980. Congress, perhaps aware regulatory agencies are sometimes

slow in issuing regulations for toxic substances,

put requirements in the statute itself; it specified toxic substances that were to be listed for

CERCLA regulation by incorporating previously

established lists, and it set reportable quantities

for many of these substances at 1 pound until EPA

issued more appropriate reportable quantities. As

of today, EPA has not modified the reportable

quantities for CERCLA carcinogens, although, as

indicated above, these regulations have been

proposed.
1 3 7

Table 3.23.—Substances Listed in CERCLA That Were Identified as Potential Carcinogens

2-Acetylamlnofluorene (Acetamide N-9H-fluoren-2-yl) Sodium chromate Methylthlouracfl

Acrylonitrile

Aldrin amitrole

Arsenic

Arsenic acid

Arsenic disulfide

Arsenic pentoxide

Arsenic trichloride

Arsenic trioxide

Arsenic trisulfide

Cacidylic acid

Calcium arsenate

Calcium arsenite

Cupric acetoarsenite

Dichlorophenylarsine

Diethylarsine

Lead arsenate

Potassium arsenate

Potassium arsenite

Sodium arsenate

Sodium arsenite

Asbestos

Auramine

Azaserine

Aziridine

Benz (c) acridine

Benz (a) anthracene

Benzene

Benzidine and its salts

Benzo (b) fluoranthene

Benzo (k) fluoranthene

Benzo (a) pyrene

Benzotrichloride

Benzyl chloride

Beryllium

Beryllium chloride

Beryllium fluoride

Beryllium nitrate

alpha-BHC

beta-BHC

gamma-BHC (Lindane)

B iS (2-chloroethyl) ether

B iS (chloromethyl) ether

B iS (2-ethylhexyl) phthalate

Cadmium

Cadmium acetate

Cadmium bromide

Cadmium chloride

Carbon tetrachloride

Chlorambucil

Chlordane

Chlornaphazine

Chloroform

Chloromethyl methyl ether (technical grade)

4-Chloro-o-toluidine, hydrochloride

Chromium

Ammonium bichromate

Ammonium chromate

Calcium chromate

Chromic acid

Lithium chromate

Potassium bichromate

Potassium chromate

Sodium bichromate

Strontium chromate

Chrysene

Coke Oven Emissions

Creosote

Cyclophosphamide

Daunomycin

DDD

DDE

DDT

Diallate

Diaminotoluene (mixed)

Dibenz (a,h) anthracene

1,2:7,8-Dibenzopyrene

1,2-Dibromo-3-chloropropane

3,3-Dichlorobenzidine

1,2-Dichloroethane

1,1 -Dichloroethylene

Dieldrin

1,2,3,4-Diepoxybutane

1,2-Diethylhydrazine

Diethylstilbestrol

Dihydrosafrole

3,3- Dimethoxybenzidine

Dimethyl sulfate

Dimethylaminoazobenzene

7,12 -Dimethylbenz (a) anthracene

3,3- Dimethylbenzidine

Dimethylcarbamoyl chloride

1,1-Dimethylhydrazine

1,2-Dimethylhydrazine

Dinitrotoluene (mixed)

2,4-Dinltrotoluene

2,6-Dinitrotoluene

1,4-Dioxane

1,2-Diphenylhydrazine

Epichlorohydrin

Ethyl carbamate (urethane)

Ethyl 4,4-Dichlorobenzilate

Ethylene dibromide

Ethylene oxide

Ethylenethiourea

Ethyl methanesulfonate

Formaldehyde

Glycidylaldehyde

Heptachlor

Heptachlor epoxide

Hexachlorobenzene

Hexachlorobutadiene

Hexachloroethane

Hydrazine

Indeno (1,2,3-cd) pyrene

Isosafrole

Kepone

Lasiocarpine

Lead acetate

Lead phosphate

Lead subacetate

Melphalan

Methyl chloride

3- Methylcholanthrene

4,4-Methylenebis (2-chloroaniline)

Methyl iodide

n-Methvl-n-nitro-n -nitrosoguanidine

Mitomycin C

1 -Naphthylamine

2-Naphthylamine

Nickel

Nickel ammonium sulfate

Nickel carbonyl

Nickel chloride

Nickel cyanide

Nickel hydroxide

Nickel nitrate

Nickel sulfate

2-Nitropropane

n- Nitrosodi-n-butylamine

n- Nitrosodiethanolamine

n- Nitrosodiethylamine

n- Nitrosodimethylamine

n- Nitrosodi-n-propylamine

n- Nitroso-n-ethylurea

n- Nitroso-n-methylurea

n- Nitroso-n-methylurethane

n- Nitrosomethylvinylamine

n- Nitrosopiperidine

n- Nitrosopyrrolidine

5- Nitro-o-toluidine

Pentachloroethane

Pentachloronitrobenzene

Pentachlorophenol

Phenacetin IARC (H)

Polychtorinated biphenyls (PCBs)

Aroclor 1016

Aroclor 1221

Aroclor 1232

Aroclor 1242

Aroclor 1248

Aroclor 1254

Aroclor 1260

1 ,3-Propane sultone

1 ,2-Propylenimine

Saccharin

Safrole

Selenium sulfide

Streptozotocin

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)

1,1, 1,2-Tetrachloroethane

1, 1,2,2-Tetrachloroethane

Tetrachloroethylene

Thioacetamide

Thiourea

o-Toluidine

p-Toluidine

o-Toluidine hydrochloride

Toxaphene

1,1,2-Trichloroethane

Trichloroethylene

Trichlorophenol (mixed)

2,4,5 -Trichlorophenol

2,4,6 -Trichlorophenol

Tris (2,3-dibromopropyl) phosphate

Trypan blue

Uracil mustard

Vinyl chloride

SOURCE NotIce of proposed rulemakmg Issued 3-16-87, federal Register 52:8140, 1987
138

Moreover, most of EPA’s activity has focused

on adjusting the RQs of substances already on the

list rather than adding to the list. The original list

was issued in April 1985 and contained 698 chemicals (307). Since then, EPA has added 19 chemicals to the list which had been added to RCRA

in January 1985 (291) bringing the total to 717.

Several sections of the 1986 Superfund Amendments and Reauthorization Act (SARA) pertain

to carcinogen testing and regulation. Section 121

requires that cleanup at Superfund sites “assures

protection of human health and the environment”

and achieves compliance with standards established under other Federal and State environmental laws (including the MCLGs of the new

SDWA amendments, formerly called RMCLs,

which are zero for carcinogens).

Section 110 requires the Agency for Toxic Substances and Disease Registry (ATSDR) of the

Centers for Disease Control to compile a list of

substances commonly found at Superfund sites

and to prepare toxicological profiles of those substances. The first such list was issued on April 17,

1987 (306), and was drawn from the 717 substances already listed as hazardous under CERCLA.

ATSDR must also initiate a testing program in

cooperation with NTP to determine the health effects of substances on the list for which there are

not adequate data. The type of testing required

is within the discretion of ATSDR, but the agency

must consider recommendations of the Interagency Testing Committee established under

TSCA. EPA is required to issue regulations under TSCA to recover the costs of testing from the

responsible parties. ATSDR must also prepare

health assessments for Superfund sites included

on the National Priorities List established by EPA

and other sites in response to petitions from affected citizens.

Section 313 of Title III of SARA which is the

Emergency Planning and Right to Know Act requires companies to report annually to EPA on

the amounts of certain substances used and discharged into various media such as air and water.

These substances are listed in Committee Print 99-

169 of the Senate Committee on Environment and

Public Works. EPA may add a substance to this

list if it causes or can reasonably be anticipated

to cause “. . . various chronic human health effects, ” including cancer.

EPA’S CARCINOGEN ASSESSMENT GROUP

At EPA, risk assessment and risk management

activities are separated more clearly than they are

at several other agencies. The Carcinogen Assessment Group (CAG) was established in 1976 to

centralize the conduct of risk assessments at EPA.

CAG is organizationally independent from EPA’s

program offices (such as the air and water programs). Its personnel are responsible only for risk

assessment, not risk management. CAG develops

most risk assessments of carcinogens at EPA, although the Office of Pesticides and Toxic Substances (administering FIFRA and TSCA) usually

conduct their own.

The first chemical given a quantitative risk

assessment at EPA was vinyl chloride, which was

assessed in 1975 for the Air Program. In its early

years, CAG worked on a number of pesticides,

including Chlordane/Heptachlor, Toxaphene,

Lindane, and Endrin. In 1977, work began on

assessment of airborne carcinogens, and in 1978

the development of the risk assessments for the

water quality criteria documents began. The latter were published in draft form in three installments in 1979, and in final form in November

1980. Between the draft and final versions, CAG

abandoned the one-hit model for extrapolating

from high doses to low doses in favor of the linearized multistage model.

A full CAG risk assessment represents a thorough review and evaluation of the carcinogenic

risks of a particular substance and averages 200

pages in length. These assessments include those

prepared for the water quality criteria documents

and the health assessment documents for EPA listing of hazardous pollutants under CAA. Other

risk assessments are much shorter, such as the

Health and Environmental Effects Profiles

(HEEPs) prepared to support decisions to list sub-
1 3 9

stances under RCRA (typically, 30 to 40 pages)

or to develop reportable quantities for hazardous

substance releases under CERCLA (10 to 20 pages)

(164).

Table 3-24 lists the substances for which the full

assessments were performed. These assessments

are all extensively reviewed, For hazard identification, CAG indicates the level of evidence in humans and animals, as well as the overall grouping in EPA’s classification scheme (see ch. 2). CAG

also performs dose-response assessments to calculate the estimated carcinogenic potency. The

slope of the dose-response line is also presented

in table 3-24. When using data from animal studies, EPA estimates the upper confidence limit of

the slope of the dose-response curve as derived

from the multistage model (see ch. 2). Calculations based on human epidemiologic data are best

estimates using a linear nonthreshold model. The

slope represents the degree of carcinogenic response associated with a given exposure. The

greater the slope, the more potent the carcinogen.

Thus exposure to a relatively potent carcinogen

(such as tetrachlorodibenzo-p-dioxin (TCDD))

OFFICE OF MANAGEMENT AND

During the 1970s, a series of executive orders

gave groups in the Executive Office of the President a role in reviewing regulatory proposals.

Over time this centralized review has greatly increased, culminating in extensive involvement in

regulation by the Office of Management and Budget (OMB) under the Reagan Administration

(219). OMB’s role has been quite controversial.

President Reagan made “regulatory relief” an

important goal for his administration early in

1981, and has issued two Executive orders on this

subject. Executive Order 12291, issued February

17, 1981, requires that agencies prepare “regulatory impact analyses” on all major regulations,

and requires that “regulatory action shall not be

taken unless the potential benefits to society for

the regulation outweigh the potential costs.” It further specified that “regulatory objectives shall be

chosen to maximize the net benefits to society”

and required, to the extent possible, that all benwill lead to a much higher probability of cancer

than exposure to the same amount of a less potent carcinogen (for example, epichlorohydrin).

To date, CAG includes 57 chemicals in the list

of full assessments complete with calculated

potencies. Most of these have relied on animal

data. Of the CAG list, nine were judged to have

sufficient evidence in humans and eight of these

nine (all except arsenic) also had sufficient evidence in animals. Three more were sufficient in

animals with limited evidence in humans, while

37 were sufficient in animals with inadequate evidence in humans. The remaining seven were

grouped in EPA classification C because the evidence was inadequate in humans and limited in

animals .18 Additional substances have been evaluated by CAG at the request of EPA program

offices, but have not received the level of review

of the 57 listed in table 3-24.

18The total is only 56 because technical grade hexachlorocyclohexane is not classified, although 3 isomers of this chemical are.

BUDGET

efits and costs be quantified in monetary terms.

This Executive order also centralized regulatory

review in OMB and required agencies to submit

proposed and final regulations and regulatory impact analyses prior to publication. Although the

legal authority to propose and issue regulations

remains with the heads of regulatory agencies, in

practice Executive Order 12291 has required agencies to receive approval from OMB prior to publication (219).

Executive Order 12498 (issued January 4, 1985)

primarily requires each agency subject to Executive Order 12291 to submit an annual agenda of

“significant regulatory actions” to OMB. OMB

also reviews agency regulations and research

proposals for compliance with the Paperwork Reduction Act (Public Law 96-511).

Proponents of OMB review argue that presidents have always taken steps they thought nec-
140

Table 3.24.—Substances Evaluated by the EPA Carcinogen Assessment Group

for Carcinogenic Potency as of Aug. 1, 1986

Level of evidencea

Grouping based Slopeb

Compounds Humans Animals on EPA criteria (mg/kg/day)-

Acrylonitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B1

Aldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Allyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B[a]P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzidene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

l,3-Butadiene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Carbon tetrachloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlordane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorinated ethanes

1,2-Dichloroethane (Ethylene dichloride) . . . . . . . . . . .

Hexachloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,1,2,2-Tetrachloroethane . . . . . . . . . . . . . . . . . . . . . . . .

1,1,2-Trichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chloroform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chromium VI..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Coke oven emissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3,3-Dichlorobenzidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,1-Dichloroethylene (Vinylidene chloride). . . . . . . . . . . .

Dichloromethane (Methylene chloride). . . . . . . . . . . . . . .

Dieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,4-Dinitrotoluene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diphenylhydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bis (2-chloroethyl) ether . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bis (chloromethyl) ether . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene dibromide (EDB) . . . . . . . . . . . . . . . . . . . . . . . . .

Ethylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Heptachlor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Heptachlor expoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorobutadiene . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorcyclohexane technical grade

alpha isomer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

beta isomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

gamma isomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorodibenzodioxin . . . . . . . . . . . . . . . . . . . . . . . . . .

Nickel refinery dust... . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nickel subsulfide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nitrosamines

Dimethylnitrosamine . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diethylnitrosamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dibutylnitrosamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-nitrosopyrrolidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-nitroso-N-ethylurea . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-nitroso-N-methylurea . . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-nitroso-diphenylamine . . . . . . . . . . . . . . . . . . . . . . . . . . .

PCBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tetrachlorodibenzo-p-dioxin (TCDD) . . . . . . . . . . . . . . . . .

Tetrachloroethylene (Perchloroethylene) . . . . . . . . . . . . .

2,4,6-Trichlorophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Toxaphene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Unleaded gasoline vapor . . . . . . . . . . . . . . . . . . . . . . . . . .

Vinyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.75X10- 2

(I)

%= Sufficient evidence; L - LlmlledevldenCe, I - Inadequate evidence.

bAnimal ~lope~areg5y0 “ppaf.b~und~l~pes b~~onthetinearfzad multistage model They arecalculatad based onanlmal oral studies, except for those indicated

by l(animal lnhalation),W(human Occupationalexpoeurehand H(human drinking waterexpoeure) Human slopes arepointeetimates based onthelinearnonthreshold

model Not all ofthecarclnogenic potencies presented In thlstablerepreaent the samedegreeof certainty.All are subject tochange as new evidence becomes avail.

able Thealope value isan upper bound inthe sense that the true value (which is unknown)is not likely to exceed the upper bound and may be much lower, with

alower bound approaching zero. Thus, the use of the slope estimate in risk evaluations requiresan appreciation for the implication of the upper bound concept as

well as the “weight of evidence” for the iikelihmd that the substance IS a human carcinogen

L

I

I

s

A

s

I

I

L

I

I

I

I

I

I

I

s

s

I

I

I

I

I

I

I

I

I

s

I

L

I

I

I

I

I

I

I

s

s

I

I

I

I

I

I

I

I

I

I

I

I

s

s

s

s

I

s

s

s

s

s

s

s

s

s

L

L

L

s

s

s

s

s

L

s

s

s

s

s

s

s

s

s

s

s

s

L

s

S-L

s

s

s

s

s

s

s

s

s

s

s

s

s

s

s

s

s

B2

B2

A

B2

A

A

B2

B2

B1

B2

B2

B2

c

c

c

B2

A

B2

B2

c

B2

B2

B2

B2

B2

B2

A

B2

B1

B2

B2

B2

c

B2

c

B2-C

B2

A

A

B2

B2

B2

B2

B2

B2

B2

B2

B2

B2

B2

B2

B2

A

0.24(W)

16

1.19X10- 2

15(H)

11.5

2.9x10- 2(W)

234(W)

8.4(W)

1.8(I)

6.1(W)

1.3OX1O- 1

1.3

9.1 X10-2

1.42x10

-2

0.20

5.73X10 -2

8.1 x10-2

41(W)

2.16(W)

0.34

1.69

1.16(I)

1.4X1O-2(I)

20

0.31

0.77

9.9X10- 3

1.14

9300(1)

41

3.5 X1 O-’(I)

4.5

9.1

1.67

7.75X10 -2

2.0

2.7

1.5

1.1

6.2x10+’

0.84(W)

1.7(W)

25.9(not by q1)

43.5(not by q1

)

5.43

2.13

32.9

302.6

4.92x10-’

4.34

1.56x10+’

5.1 X10-2

1.99X10-2

1.13

1.1 X10-2

3.5X10 -3

SOURCE: Environmental Protection Agency
141

essary to control executive branch agencies (38).

Further, even in a technological age, not all decisions are technical ones, and regulatory decisions

involving both technical and policy decisions

should be subject to the President’s oversight.

OMB’s role has also been supported as necessary

to achieve reform of the regulatory process, ensure “good regulation, ” reduce the costs of regulation, curb overzealous agencies, and gain control over a potentially expensive process. By

reviewing regulations and requiring cost-benefit

analysis, OMB forces agencies to confront problems of “covert redistribution and overzealous

pursuit of agency goals, ” thus making agencies

accountable to the President (38).

But OMB's review of agency actions has generated criticism (206,208,225). These criticisms

raise constitutional issues, other legal issues, and

more public policy issues about OMB’s role in reviewing agency decisions.

Even with presidentially delegated authority,

it may be unconstitutional for OMB to control

decisions delegated by Congress to executive

branch agencies (152). Furthermore, if OMB, in

reviewing and approving or disapproving regulations, uses considerations not authorized by statute, its actions may not be permissible, especially

when this conflicts with expressed congressional

intention (152). In addition, since congressional

committees have documented some evidence of

ex parte and secret contacts between OMB and

regulated industries (206,225), several commentators suggest this undermines the Administrative

Procedure Act’s public participation requirements

for informal rulemaking (132,153).

Critics have also argued that delays imposed

by OMB

. . . are paid for through the decreased health

and safety of the American public . . .; [that

OMB review] . . . places the ultimate rulemaking decisions in the hands of OMB personnel

who are neither competent in the substantive

areas of regulation, nor accountable to Congress

or the electorate in any meaningful sense . . .

[and that Executive Order 12498] . . . allows

OMB to cut off investigations before they even

begin, making it nearly impossible to attack

OMB’s decision that a potential rule is “unnecessary” (132).

One problem with the regulation of carcinogens

discussed in this chapter involves delays in regulating problematic substances, delays between the

time a statute is passed and the time an agency

is authorized to regulate toxic substances, and delays between the time an agency has information

that a substance is a carcinogen and the issuance

of regulations. In recent years there have been additional delays because of OMB’s review of major regulations.

EPA has compiled data on the average number of days rules are extended past the time limits

specified by Executive Order 12291, for example,

30 days for a minor rule and 60 days for a major

rule (one with an impact on the economy of $100

million or more).

The average extension in April 1985 was

slightly under 50 days; previous peaks were near

100 days . . . [thus] . . . OMB holds minor rules

for an average of over two months [rather than

the 10 days Executive Order 12291 specifies for

minor rules] and major rules for over four

months [rather than the 60 days specified by Executive Order 12291] (225).

This average conceals some much longer delays

involving rules that generated considerable dispute between OMB and some of the regulatory

agencies:

●

●

●

●

EPA’s proposed ban on certain uses of asbestos and its phase-out over time of most

other uses of asbestos were delayed more

than 1 year.

OMB delayed by at least 5 months EPA’s recommended maximum contaminant levels

“for approximately forty organic and inorganic chemicals under the authority of the

Safe Drinking Water Act . . .,” leading Senator Durenberger to introduce an amendment

to require OMB to complete its review of the

RMCLs by a certain date.

For EPA’s proposed National Priorities List

under Superfund, OMB forced EPA to choose

between “delaying an entire executive action

or sacrificing a part of it to gain OMB’s approval of the major portion. ”

Eleven proposed New Source Performance

Standards for new and modified stationary

air pollution sources, all submitted to OMB

3 to 13 months ahead of a statutory dead-
1 4 2

●

line, were delayed beyond that time. Fourteen months of the delay in publishing these

rules were due to OMB’s review under Executive Order 12291.

High-level radioactive waste storage rules

proposed by EPA were delayed by 1 year,

leading to a suit by the Environmental Defense Fund against both OMB and EPA for

missing a statutory deadline. Several congressmen filed an amicus brief on the side of

the Environmental Defense Fund (225).

Shortly after the report from the Senate Committee on Environment and Public Works was

completed, the District Court for the District of

Columbia ruled that OMB has no authority to delay the issuance of the final rule which was the

subject of suit or to delay issuance of any other

rules “subject to statutory or judicial deadlines

under the Hazardous and Solid Waste Amendments of 1984” (225).

Under the Paperwork Reduction Act, OMB

also reviews research proposals that involve government survey research. One example of OMB’s

involvement in a study concerning a carcinogen

was a NIOSH proposal to evaluate the risk to human beings from MBOCA. This study was delayed by OMB for 6 months. This was not a regulation, but a proposed study of human beings,

when NIOSH already had evidence that MBOCA

was carcinogenic in three animal species (207).

The Paperwork Reduction Act mandates that

agencies obtain approval from OMB concerning

these recordkeeping requirements. In some cases,

regulations will require that records be kept by

industry.

POSSIBILITIES FOR IMPROVING AGENCY TIMELINESS

This chapter has described the activities of the

Federal agencies in assessing and regulating carcinogenic chemicals. A number of chemicals have

been regulated for carcinogenicity and exposures

have been reduced or eliminated. In some cases,

the agencies have determined that the risks posed

by particular chemicals are low and that there was

no need to regulate. In other cases, the agencies

are still obtaining toxicity and other information

needed to regulate or are developing the analyses required by their statutes and by OMB. Finally, there probably are cases in which the necessary data have been collected, the analyses have

been performed, and agency staff are simply waiting for decisions whether to regulate.

A constant in this chapter’s overview of Federal activities is that the regulatory process is often

a lengthy one.19 To force regulatory action, Congress has legislated a variety of statutory mechanisms. These include statutory deadlines, congressionally mandated regulations, and institutional

review and response mechanisms.

19Concern about regulatory delay is not new. See, for example)

a 1977 paper by Sidney Wolfe (364).

The most common of these have been statutory

deadlines; although they have led to regulatory

action, they are also frequently missed by the

agencies. A report on the statutory deadlines in

15 environmental protection statutes affecting

EPA found approximately 328 deadlines for setting regulations, issuing reports and studies,

achieving compliance, setting guidelines, and accomplishing other tasks. The report estimated that

14 percent of these deadlines were actually met.

However, while the original deadlines were

missed, an estimated 41 percent of the EPA actions that were required had been completed by

September 1985. The report concluded that, while

statutory deadlines have brought about action by

EPA and secured advances in environmental protection, deadlines are not sufficient to speed action. Moreover, Congress sets more deadlines for

EPA than the Agency can meet, thus diluting the

effectiveness of any one deadline, and it often sets

unrealistic deadlines (48).

Congress has also mandated particular regulatory requirements. For example, in section 6 of

the Toxic Substances Control Act, Congress ordered EPA to regulate the disposal of PCBs within

6 months and to prohibit further manufacture, except in closed systems, within 1 year of enactment.
-, 143

Another form of mandate is to

agency to regulate a specified list of

require an

chemicals.

For instance, in the Occupational Safety and

Health Act, Congress ordered OSHA to adopt

within 2 years established Federal occupational

health and safety standards and the standards

adopted by consensus standards organizations. In

CERCLA, EPA was required to adopt a list of

chemicals that had already been regulated under

other environmental laws. In the 1977 Clean

Water Act amendments, Congress codified a list

of 65 classes of pollutants that had been developed for a consent decree settling a lawsuit

directed against EPA for failing to regulate water

pollutants. For the deadlines set in the 1984 RCRA

amendments, Congress added “hammers’ ’-statutory bans that take effect if EPA misses deadlines;

depending on one’s perspective, this combines either the best and worst of these two approaches

to congressional mandates.

One final mechanism is requiring agencies to

consider or, stronger still, respond to recommendations of another agency or organization. For

example, OSHA is to consider the recommendations of NIOSH when developing new occupational health and safety standards. Stronger is the

requirement that the Mine Safety and Health

Administration must respond within 60 days to

NIOSH recommendations. However, NIOSH has

not yet sent any recommendations to MSHA that

trigger this requirement. Under TSCA, EPA must

respond to ITC’s nominations of chemicals for

toxicity testing, although one possible response

is a decision not to require testing. In fact, the lists

of chemicals recommended by ITC have dominated EPA activities on the testing of existing

chemicals.

In the Safe Drinking Water Act of 1974, Congress required EPA to commission a study on

drinking water by NAS. The study was to identify potentially harmful contaminants in drinking water and make recommendations concerning national standards for maximum contaminant

levels. It was expected that EPA would use those

recommendations. However, the NAS study decided that it was not appropriate to recommend

contaminant levels, concentrating instead on developing information on potential toxic effects.

Later amendments to the SDWA removed the requirement for EPA response to the NAS reports.

None of these mechanisms is a panacea. Congressional deadlines and mandated lists may force

action, but also may divert regulatory agencies

from chemicals and regulations more in need of

regulation. Lists, in particular, may immerse Congress in extensive detail on particular chemicals.

An institutional mechanism allows a group of experts or a scientific agency to sort through the lists

of particular chemicals and recommend the ones

of highest priority. On the other hand, establishing regulatory implications may mean that the recommending group should have a formal process

for decisionmaking, including response to public

comments. Establishing such a process might slow

the whole operation down. In addition, establishing a regulatory linkage might dissuade scientists

from participating who do not want to be involved in decisions with regulatory implications.

Finally, such recommendations may inappropriately redirect agency priorities and create pressure for regulatory action. Such regulatory action

may not always be necessary and may impose

costs on regulated industries.
Chapter 4

The National Toxicology Program
CONTENTS

Page

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................147

The Need for Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................147

History of Major Federal Efforts in Carcinogenicity Testing . .................148

NCI Testing Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................148

Establishment of the National Toxicology Program . . . . . . . . . . . .............149

Organization of NTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ... ... ... ..150

Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. .. ... .. <.....150

Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........................151

Nominating Chemicals for Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ....152

Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......152

NTP Carcinogenicity Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........154

Methods of Study and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...154

Observations on the NTP Nomination and Selection Process . ................157

Criteria for Nomination and Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...157

Number Source, and Disposition of Nominated Chemicals . ..,............160

Duration of Testing Process Stages . . . . . . . . . . ............................161

Case Study in Nomination and Selection: the Benzodiazepines . .............161

Mutagenicity Testing: Correlation With Animal Carcinogenicity . .............164

Relation of Chemical Carcinogenicity in Animals to Cancer in Humans. . ......166

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................167

Figures

Figure No. Page

4-1. National Toxicology Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........150

4-2. NTP Chemical Nomination and Selection Process , . . . . . . . . . . . . . . . . . . . . ..153

Tables

Table No. Page

4-1.

4-2.

4-3.

4-4.

4-5.

4-6.

4-7.

Costs of NTP Studies of Fiscal Year 1986 . .............................152

NTP Chemical Selection Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...158

Source of Nomination of Chemicals for Mutagenicity and Bioassay Testing

by NTP by Year . . . . . . . . . . . . . . . . . . . . . . . . ............................159

Initial Response of Board of Scientific Counselors to Actions of the

Chemical Evaluation Committee on 164 Chemicals, Fiscal Year 1982-

Fiscal Year 1986 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................161

Time (in months) From Nomination of Chemicals Considered by the

Chemical Evaluation Committee in Fiscal Year 1981 and Fiscal Year 1982

to Intermediate and Final Points in the Process of Approval

for Testing by NTP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............162

Status of Chemicals Approved for Testing by the NTP Executive

Committee in Fiscal Year 1981 or Fiscal Year 1982 (Status as of January

1987) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...162

History of Agency Priority Chemicals (Status as of April 1987) ...........162
Chapter 4

The National Toxicology Program

BACKGROUND

In the 1960s, government agencies, especially

the National Cancer Institute (NCI), used animal

tests to predict carcinogenicity, though at first to

learn more about the relation between chemical

structure and carcinogenicity and not for regulatory purposes. In November of 1978, the Secretary of the then Department of Health, Education,

and Welfare (DHEW) established the National

Toxicology Program (NTP), aware of the need

to test chemicals for carcinogenicity (and other

toxic end points), the limited ability of existing

programs to keep up with the demands of new

legislation, and the lack of coordinated testing.

Cancers often develop more quickly in animals

than in humans, although not in relation to lifespan. Still, animal tests take time, 2 years of exposure for rodents, for example, and the tests are

costly. In the 1970s, based primarily on the work

of Bruce Ames, a high correlation was found between tests for mutagenicity of chemicals in

microorganisms and carcinogenicity in animals

(217). These genetic toxicology tests, and a second generation of short-term tests that followed,

can be performed in days rather than years, and

are much less costly than animal tests. The hope

was expressed in DHEW that “by 1985 . . . better test systems will begin to replace the tedious

and costly animal assay now required” (60). This

THE NEED FOR TESTING

In 1980, NTP contracted with the National Research Council (NRC) to conduct a study, with

a charge “to characterize the toxicity-testing needs

for substances to which there is known or anticipated human exposure” (140). From approximately 5 million chemicals the Study committee

compiled a list of 53,500 chemicals in 7 categories of human exposure. By systematic sampling

of chemicals in each category, 675 chemicals were

selected from this list. Multiple sources were examined to determine whether toxicity testing had

optimism has proved unfounded; the new tests

have not proven superior to the original Ames

test, which itself is an imperfect predictor of animal carcinogenicity.

Most animal carcinogenicity testing was transferred from NCI to NTP in 1981. In the first part

of this chapter, the origins, support, and organization of NTP are described and the NTP process of selecting chemicals for testing is analyzed.

A discussion follows of the relation of the results

of the short-term tests to those of animal carcinogenicity studies, and finally the predictability of human carcinogenesis from animal tests.

Some of these issues were discussed in chapter 2;

they will be examined here only with regard to

NTP.

Since this background paper focuses on the relation of carcinogen studies to regulatory decisions

and the research activities of NTP, many of them

conducted with the National Institute of Environmental Health Sciences (NIEHS) and the National

Center for Toxicology Research (NCTR), receive

scant consideration. NTP’s goals include understanding the mechanisms by which cancers are initiated and propagated and developing better and

quicker methods of determining chemicals’ carcinogenicity.

been conducted on these 675 chemicals. Extrapolating to the entire list, the committee estimated

that there was no toxicity information on 38 percent of pesticides, 56 percent of cosmetic ingredients, 25 percent of drugs and excipients used in

drug formulations, 46 percent of food additives,

78 percent of chemicals in commerce of which

over 1 million pounds were produced in 1977, 76

percent of chemicals of which under 1 million

pounds were produced, and 82 percent of chemicals whose production status was unknown or in147
148

determinable.’ Tests for chronic toxicity were performed most frequently on drugs (39 percent) and

least frequently on chemicals in commerce (3 to

4 percent). From the list of 675 chemicals, the

committee selected 100 on which some toxicity

information was available; 10, 15, or 20 were

selected from each of the 7 categories to deter1Chemicals that were environmental decomposition products,

manufacturing contaminants, or natural substances were not systematically included.

mine the type and adequacy of testing. The report concluded, “Only about 8 percent of the tests

met the standards of the reference protocol guidelines, and about another 19 percent were judged

to be adequate.” In discussions with OTA in 1986,

Dr. Ernest McConnell, Director of the Toxicology Research and Testing Program, which is the

principal NIEHS component of NTP, estimated

that approximately 1,000 chemicals with high human exposure potential should be tested (120).

HISTORY OF MAJOR FEDERAL EFFORTS IN

CARCINOGENICITY TESTING

NCI Testing Activities

NCI began animal testing of chemicals for carcinogenicity in 1961. Elizabeth Weisburger, one

of NCI’s charter researchers, described the aims

of the project:

There was no mention of a program for largescale bioassay of industrial or environmental materials. To quote, “first priority should be given

to chemicals most likely to make a contribution

to our knowledge of the etiology of cancer and

deepen our understanding of their mode of action”

(357).

In the late 1960s, NCI responded to demands

for testing chemicals in the environment. In 1970,

for instance, it initiated contracts for studies of

40 pesticides approved for use in the United States.

Appropriations under the National Cancer Act

of 1971 provided sufficient funds to initiate a

greater number of long-term animal studies,

which reached a peak of 200 in 1972. The increase

was so rapid that the consequences were not fully

appreciated. “Neither NCI nor the prime contractor had enough assistance in pathology to examine all the microscope slides which resulted” (357).

The backlog of chemical studies was not eliminated until 1979.

Government laboratories could not accommodate the volume of testing. Moreover, these laboratories were designated primarily for basic research, not for the routine testing of chemicals for

toxicity. 2 Consequently, most of the animal tests

were performed contractually by nongovernment

laboratories. In 1973, NCI contracted with Tracer

Jitco, Inc., to oversee the bioassay operations of

the other contractors. Tracer Jitco also supplied

data on chemicals being considered for testing to

the Chemical Selection Working Group (CSWG)

in NCI, which was responsible for the actual selection. A General Accounting Office report (201)

found fault with this system. As a result, NCI instituted stricter monitoring of Tracer Jitco and its

other contractors.

Despite concern over carcinogens in the environment, which contributed to the flood of testing

in the 1970s, the process of notifying regulators

was neither easy nor uncontroversial. Publications

in the scientific literature indicating the carcinogenicity of 1,2-dibromoethane and l,2-dibromo-3-

chloropropane (in 1973) “led to no consternation

or notice among regulatory agents [sic]” (357). To

overcome this, NCI issued a “memorandum of

alert” in 1975, when it became evident that trichloroethylene (TCE) was causing an increase of

liver tumors with lung metastasis in some animals. According to Weisburger:

‘In a congressional hearing in 1981, Dr. Vincent DeVita, director of NCI, commented that NC] “never developed this [animal testing] program to be a source of information for the regulatory agencies. Therefore, when suddenly there was pressure for us to provide

routine information, we were not able nor properly constructed to

do that” (213).
149

Criticism of the “memo of alert” was so great

that this mechanism was not used again. Instead,

the complete record of any bioassay was compiled in a Carcinogenesis Technical Report; draft

versions of the reports were sent to the regulatory agencies for their information prior to release to the public (357).

The furor over the preliminary publication arose

because the Food and Drug Administration (FDA)

could no longer consider TCE as an acceptable

solvent for decaffeination under the Delaney

clause. According to Weisburger, NCI staff were

unaware that it was used for that purpose.

Problems of communication generally intensified as more agencies became involved in regulating carcinogens. These agencies had the capability to perform tests for carcinogenicity or the

authority to require industry to do so. No channels existed for agencies to communicate about

the chemical tests that were in progress or recommended; duplicate testing sometimes resulted.

Sometimes testing was beyond the capability

of an agency, yet information on the toxicity of

a chemical would have been helpful in making

regulatory decisions. No formal mechanism existed for regulatory agencies to request NCI testing. “The entire process [of test selection] was

quite informal with discussion among [NCI] staff

only” (357).

Establishment of the National

Toxicology Program

NTP was established in November 1978 by the

Secretary of the then Department of Health, Education, and Welfare “to strengthen the Department’s activities in the testing of chemicals of public health concern, as well as in the development

and validation of new and better integrated test

methods” (268). To accomplish its goals, NTP was

“comprised of the relevant [Public Health Service] activities” within FDA (namely, NCTR), NCI,

Centers for Disease Control (CDC) (namely, the

National Institute for Occupational Safety and

Health (NIOSH)), and the NIEHS. Dr. David

Rail, Director of NIEHS, was named Director of

NTP, reporting to the Assistant Secretary for

Health. The organizational structure of NTP is

shown in figure 4-1.

A 1981 paper prepared by NIEHS as background for a congressional hearing on NTP (90),

commented that NTP was established as an interim measure because there was disagreement

within DHEW as to how testing should be organized. The NTP Director was expected to coordinate the activities of various departmental components, but he could not “allocate resources,

either funds or personnel, to areas of greater need

and priority, except through agreement with the

other agency heads.” At the hearing, Dr. Rail and

Dr. Ronald Hart, director of NCTR, indicated

that they were in frequent communication and

that there was “a minimal amount of confusion”

(213). Dr. Rail also delineated NTP’s role from

that of the regulatory agencies. NTP’s responsibility was in risk identification and quantification,

primarily in animals; the agencies’ responsibilities were determining human exposures and evaluating human risks and benefits. In response to a

question from Congressman Albert Gore, Dr. Rail

indicated that the allocation of so much of NTP’s

budget on testing was not optimal and that more

should be devoted to developing better methods.

Dr. Hart, Dr. Vincent P. DeVita, Director of NCI,

and Dr. Millar, Director of NIOSH, emphasized

NTP’s role in testing chemicals.

In October 1981, the Secretary of the Department of Health and Human Services (DHHS)

granted NTP permanent status. The funding arrangements remain voluntary. As stipulated in the

original announcement, memoranda of understanding are signed by the head of each cooperating agency and the NTP Director, specifying the

resources to be devoted to NTP, and identifying

by organizational title the supporting elements of

the participating agencies and their responsibilities (e.g., specific studies to be undertaken). With

the transfer of the NCI Carcinogenesis Testing

Program to NIEHS in July 1981, the vast majority

of funds (87 percent of the NTP budget at the

time) come from NIEHS. Dr. David Rail determines how much NIEHS will contribute to NTP,

as the heads of NCTR and NIOSH determine their

agencies’ contributions. At the present time, most
150

Figure 4-1 .–National Toxicology Program (NTP)

SOURCE: National Toxicology Program, 1987,

of the staff assigned to NTP comes from NIEHS,

consistent with the contribution NIEHS makes to

NTP’s budget. The memorandum of understanding between NIEHS and NTP indicates that the

NIEHS Toxicology Research and Testing Program

is “dedicated to the National Toxicology ProORGANIZATION OF NTP

Structure

The NTP Steering Committee was formed in

1980 to promote “cooperative working relationships” among the contributing DHHS agencies.

The committee consists of the NTP Director and

the heads of NIEHS, NCTR, and NIOSH. It meets

three to four times yearly to review programs and

gram.” It lists the NIEHS program elements and

key scientists committed to NTP, accepts responsibility for administration, and indicates its contributions to NTP in person-years, budget, and

space (234).

projects, resolve interagency problems, and make

agency allocations for approved chemical toxicological studies (257).

The documentation of NTP activities and plans

is accomplished through an annual plan, as stipulated by the Secretary of DHEW (268), who also

specified the plan’s contents: information on cur-
151

rent toxicology testing capacity and capacity in

the coming year on plans for test development and

validation, on the compounds to be tested, and

on the regulatory and scientific opportunities that

were considered in developing the plan. The Secretary established an Executive Committee to approve and monitor the annual plan. This committee consists of the heads of four regulatory

agencies—the Environmental Protection Agency

(EPA), FDA, the Occupational Safety and Health

Administration (OSHA), and the Consumer Product Safety Commission (CPSC)—and the heads

of the National Institute of Health (NIH), NCI,

NIOSH, and NIEHS. On April 1, 1987, the Executive Committee voted to add the Agency for

Toxic Substances and Diseases Registry to its

membership. In addition, the Assistant Secretary

for Health of DHHS is a nonvoting member and

the Director of NCTR is a nonvoting consultant.

In testimony before Congress in 1980, Dr. Rail

indicated that he had proposed that the Departments of Energy and Agriculture join the NTP Executive Committee (205). This has not happened.

The composition of the Executive Committee provided the regulatory agencies outside of DHHS

input to the planning and operation of NTP.

These agencies, partly through the Executive

Committee, have an important role in NTP activities, particularly in setting priorities for chemicals studies and in coordinating testing. In 1980,

NTP reported that several chemicals recommended for industry testing by the Interagency

Testing Committee (ITC) under the Toxic Substances Control Act (TSCA) were under test or

scheduled for test by NTP (253). Since 1980, NTP

has had a liaison representative with ITC to avoid

redundancy of testing.

Resources

The number of chemicals tested depends primarily on the resources available. The budget for

NTP activities (including NCI’s contribution for

testing) increased approximately 40 percent between 1979 and 1981. From fiscal year 1981 to

1987 the total NTP budget rose (including contributions from NCTR and NIOSH) from $70.5

to $77.9 million. After adjustment for inflation,

this represents a small decline. The budget percentage devoted to testing fluctuated between 66

and 74 percent. Remaining funds were used for

developing and validating testing methods and for

management expenses. After NTP was established

in 1978, participating agencies expected that they

would receive larger appropriations to allocate to

testing under NTP.

Since 1981, the inclusion of additional shortterm tests, more detailed prechronic testing, and

the use of three experimental doses and controls

instead of two in chronic studies, which entails

a greater number of animals, has increased the

costs of testing a single substance. To resemble

human exposures more closely, inhalation studies

are being used more frequently than in the past.

These studies entail special equipment and are the

most costly of the chronic studies. Expenditures

for analytical chemistry, a chemical repository,

and auditing of data and laboratory practices have

also increased.

The costs of various types of tests in fiscal year

1986 are shown in table 4-1. The prechronic study

(to identify target organ toxicities and determine

the doses to be used in the chronic phase) and the

chronic study of a single chemical often cost over

$2 million. (The cost of the Salmonella assay or,

“Ames” test, is about $3,300.) In fiscal year 1987

an estimated 43 chemicals will be in the prechronic

phase of testing, including beginning studies

(“starts”) on an estimated 30, and 137 will be in

the chronic phase, including starts on an estimated

7.

NCTR’s budget allocated to NTP activities fell

from $6.1 million in fiscal year 1981 to $4.3

million in 1986, with only $1 million estimated

for 1987. As a result of the budget reductions recently necessitated by the Gramm-Rudman-Hollings Act, NCTR discontinued long-term animal

tests under NTP on one antihistamine and continued two others only when NTP through NIEHS

agreed to fund their completion. NCTR is testing other chemicals through NTP. NIOSH’s allocations to NTP have fluctuated considerably between 1981 and 1986: $4.1 million in 1981 (the

highest allocation), $1.8 million in 1985 (the

lowest), and $3.7 million estimated for 1987. Not

all of these funds are used for testing. Staff scientists who serve as chemical managers at NCTR

and NIOSH continue to design protocols for test-
752

Table 4-l.—Costs of NTP Studies of Fiscal Year 1986

Type of study Cost per studya

Mutdagenicity;

Drosophila . . . . . . . . . . . . . . . . . $ 11,083

Salmonella. . . . . . . . . . . . . . . . . 3,328

Cytogenetics . . . . . . . . . . . . . . . 12,932

Mouse Iymphoma . . . . . . . . . . . 6,500

Fertility & Reproduction:

Fertility assessment. . . . . . . . . 80,300

Sperm morphology . . . . . . . . . . 5,300

Teratology:

Conventional . . . . . . . . . . . . . 68,000

Inhalation . . . . . . . . . . . . . . . . 350,000

Prechronic Studies:b

Low rangec

Dosed feed/dosed water . . . . . 440,000

Gavage . . . . . . . . . . . . . . . . . . . . 505,000

Skin paint. . . . . . . . . . . . . . . . . . 520,000

Inhalation . . . . . . . . . . . . . . . . . . 655,000

Chronic:d

Dosed feed/dosed water . . . . . 1,210,000

Gavage . . . . . . . . . . . . . . . . . . . . 1,460,000

Skin paint . . . . . . . . . . . . . . . . . . 1,460,000

Inhalation . . . . . . . . . . . . . . . . . . 1,960,000

High rangec

730,000

785,000

785,000

1,285,000

1,860,000

1,860,000

1,960,000

2,460,000

aCosts include actual contract award, support contracts, plus in-house operating costs,

blncludes studies such as 14 day, 90 day, sperm morphology, va9inal cYtolo9Y,

clinical chemistry, urinalysis, hematology, chemical disposition, in-vivo shortterm characterization.

ccosts based on range of awards made in fiscal year 1986. Where awards were

not made in some of the categories, estimates were prepared,

dThree dose levels, one interim sacrifice, clinical chemistry and possibly hematology.

SOURCE: National Toxicology Program,

ing selected chemicals, but NIEHS provides most

of the funds and staff for NTP testing.

Nominating Chemicals for Testing

NTP invites the nomination of chemicals for

testing from any source. In fiscal year 1982, the

NTP Executive Committee agreed to an FDA request that each participating agency could nominate one “priority” chemical per year for carcinogenicity testing. FDA wanted to ensure that

more chemicals of concern be tested. The “agency

priority” chemicals would be placed on a “fast

track” for selection, as will be discussed further.

If an agency fails to nominate a chemical in one

year, it can still only nominate one the following

year. Only five chemicals have been nominated

by this fast-track route. They are D&C Yellow

No. 11 (FDA), gallium arsenide (NIOSH), 2-butoxyethanol (CPSC), t-butylhydroquinone (FDA),

and styrene (NIOSH). Nominating a chemical in

this way does not preclude an agency from nominating other chemicals by the normal process in

the same fiscal year. Any organization or individual can nominate as many chemicals as desired. The NTP Chemical Selection Coordinator

and an Assistant to the Director of NTP remove

from further processing chemicals that have already been or are being tested, or have been

previously rejected for testing (although renominations that are submitted with additional information may be considered). “Draft executive

summaries” are then prepared on the remaining

chemicals, except those that have been nominated

for genetic toxicology testing only. For these, the

nominations are presented directly to the Chemical Evaluation Committee (CEC) with summary

data on production levels.

Until 1984, the summaries were prepared by

NCTR. In 1984, NTP contracted with Dynamac

Corporation (Rockville, Maryland) to prepare the

draft executive summaries. After selecting Dynamac as the successful bidder, one of the unsuccessful bidders objected to the award, claiming

that Dynamac did not qualify as a small business.

This delayed Dynamac’s start and resulted in a

backlog of nominations. The summaries prepared

by Dynamac include information on chemical and

physical properties, production, use, exposure,

toxicology, and related regulatory activity (26).

They are presented to the CEC, which makes the

initial recommendation in selecting chemicals for

testing. The nomination and selection process is

diagramed in figure 4-2.

Selection

In congressional hearings for fiscal year 1981

appropriations, the directors of NCI and NTP

proposed that funding be sufficient to begin 100

animal tests on chemicals in 1981. Dr. Rail proposed that this level of starts be maintained each

year until 1984. At that time he said, “implementation of the Toxic Substances Control Act will

allow us to begin to decrease the number of chemicals tested” (205). In commenting further on

industry’s role at the hearings, Dr. Donald Fredrickson, then NIH Director, said that it was impossible to attach commercial interests to chemicals that had been in the common domain for

many years. He anticipated that when the Toxic

Substances Control Act was “fully implemented,

however, the NTP should be able to scale down”
153

Figure 4-2.—NTP Chemical Nomination and Selection Process

Nomination

- Public

I

I

I

I

T & t

Withdraw

SOURCE: National Toxicology Program, 1987.

(205). The budget increase that would have supported 100 test starts annually never materialized

and NTP had more nominated chemicals than it

could study at that time (26).3 Under such circumstances, nominations of chemicals had to be considered carefully, and priorities for testing established.

The Executive Committee, composed of representatives from CPSC, EPA, FDA, OSHA, NCI,

NIEHS, NIOSH, NCTR, and NTP, meets about

3After it became evident that funds would not be available to support as much testing as was anticipated, the participating agencies

were each asked to designate the 10 highest priority chemicals from

among the 140 chemicals that had already been recommended for

testing by CEC by March 1980. Thirty-nine were chosen and approved by the NTP Executive Committee; for scientific reasons, not

all were tested. Approximately 50 additional chemicals among the

140 were also approved by the NTP Executive Committee for testing by mid-1982.

four times a year to evaluate the drafts and recommend the types of testing, if any, to be performed along with their priorities. By having each

member serve as a primary or secondary reviewer

of each chemical nomination, NTP is assured of

better participation from the other agencies. The

CEC makes the final decision about nominated

chemicals only for genetic toxicology testing. Approximately 2 months after a chemical is considered by the CEC, it is listed in the Federal Register,

together with the Executive Committee recommendation. Its decisions on chemicals nominated

only for genetic toxicology testing are not published in the Federal Register. Thirty days are

given for responses but all responses are considered regardless of the date of receipt.

The executive summaries are revised to include

public comments, and then submitted to NTP’s

Board of Scientific Counselors. The Board is com-
154

posed of eight nongovernmental scientists appointed by the Assistant Secretary for Health for

staggered 4-year terms. It meets two or three times

a year in public sessions. The Board’s recommendations and suggested testing priorities, are incorporated into the executive summaries and submitted to the NTP Executive Committee. Notice

of the one priority chemical that each regulatory

agency is permitted to nominate each year is not

sent to the Board, but goes directly to the Executive Committee from the CEC. Neither the CEC

nor the Executive Committee have rejected any

of the five agency priority nominations submitted

to date.

The NTP Executive Committee makes the final decision on prechronic and chronic testing and

testing priorities for those chemicals recommended

by the CEC or Board. It has done this by selecting “priority chemicals” for testing each year commensurate with NTP resources. It does not set priorities among these chemicals at the time of

selection. Notifications on chemicals CEC recommends for chemical disposition, genetic toxicology, or reproductive studies are not sent to the

Executive Committee but to the program leaders

in NTP-NIEHS responsible for corresponding

areas; they make the decisions about testing. They

also can select other chemicals for testing within

their program subject to budgetary limitations.

Once chemicals are approved by the Executive

Committee, the NTP Steering Committee refers

them to one or more of the three constituent agencies of NTP (NIEHS, NCTR, and NIOSH) where,

in turn, they are assigned to chemical managers.

NTP CARCINOGENICITY TESTING

Methods of Study and Analysis

Before a bioassay for carcinogenicity can be

performed, preliminary information is needed.

This is obtained by gathering data on chemical

exposures and from studies done elsewhere. When

there is some question about biological availability, chemical disposition and pharmacokinetic

studies are conducted prior to prechronic and

These scientists develop testing protocols to submit to the Toxicology Design Review Committee (TDRC), a group of NTP scientists representing different disciplines. The chemical manager

of the TDRC can also recommend that testing not

be pursued, because, for instance, of technical

difficulties, unavailability of chemicals, or adequate outside testing. This happens infrequently.

Based on the studies under their supervision, the

chemical managers can nominate additional chemicals for study or additional studies on chemicals

they are already testing.

The NTP Technical Bulletin provided information on the Executive Committee’s selections and

plans for testing, and on the results of mutagenicity tests. More than 7,000 people received this

bulletin, which was discontinued in 1983. According to NTP staff, a similar publication would be

useful, to present the results of prechronic studies

and plans for chronic studies and other information for public information and comment. NTP

is considering a plan to publish the experimental

design of chronic studies in the Federal Register

to permit responses from interested readers. Beginning in 1986, NTP publicly named chemicals

on which short-term toxicology studies had been

completed, specifying the administration route,

species, and duration for proposed prechronic

studies on these chemicals; the names of the responsible chemical managers were also specified.

Comments were invited on chemicals’ current production, uses, exposure levels, and toxicology

data, to help NTP decide whether additional

studies, including long-term toxicology and carcinogenicity studies, are needed (254).

chronic studies. Based on information gathered

before the prechronic studies, and also on budgetary constraints, chemical testing may be deferred or dropped. Such decisions have been made

for 37 chemicals since 1982.

Chemical Disposition

Information must be obtained on how a chemical selected for testing is absorbed through vari-
ous administration routes, for example through

gastrointestinal and respiratory tracts and skin.

The route of administration usually selected for

bioassay is the route through which humans will

most likely be exposed, unless the compound cannot be absorbed by that route. Such a finding may

also lead to a decision not to test.

Pharmacokinetic Studies

Determining the rates of absorption and conversion to other compounds at various doses helps

in selecting the doses for prechronic and chronic

studies. When several related compounds in a

class are tested it is also important to know

whether they are converted to a common metabolite; it may then be possible to test only one member of the class.

Prechronic Studies

In prechronic studies, animals (usually mice and

rats) are administered various doses of the chemical first for 14 days and then for 13 weeks, to

evaluate organ-specific pathological changes,

body and organ weight changes, clinical signs,

and other indicators of toxicity. From the evaluation, an estimated maximum tolerated dose

(EMTD) is determined. The EMTD is usually the

highest of three doses administered in the chronic

studies that follow. The Ad Hoc Committee of

the NTP Board of Scientific Counselors recommended that when results are nonlinear, additional intermediate doses should be used, and that

consideration should be given to having the lowest

dose in a chronic study in the range of human exposure (258). Such a dose is likely to yield a significant number of tumors only when larger doses

cause tumors in a very high percentage of animals,

as occurred in the original chronic inhalation

studies on methylene chloride. Over half the male

and female mice developed lung tumors at 2,000

ppm, and over half of them developed liver

tumors at 4,000 ppm. NTP has decided to conduct additional studies in female mice, probably

using doses of 2,000, 1,000, and 500 ppm to elucidate the chemical’s mechanism of action. The

OSHA maximum peak dose for 5 minutes in any

2-hour period is 2,000 ppm, and for an 8-hour

time-weighted average is 4,500 ppm; its accept155

able ceiling is 1,000 ppm. NIOSH-recommended

exposure limits are lower (131).4

Chronic Studies

In the chronic studies, the chemical is usually

administered to both sexes of mice and rats for

2 years, at which time the surviving animals are

sacrificed. Usually 60 animals of each sex and species receive each dose of the chemical for the duration of the study; an additional 60 of each sex

and species serve as controls, receiving no chemical. Usually 10 of each experimental group (defined by species, sex, and dose) are sacrificed at

15 or 18 months to determine whether any tumors

have already developed.

Evaluation of Results

The incidence of tumors in each group is determined, as are nontumorigenic effects, through

necropsy and histopathologic examination. In the

study of a single chemical, about 40,000 tissue

selections may have to be examined (93). Omitting examination of certain sections succeeded in

reducing costs. However, the calendar time required for testing was longer because of added review steps. Therefore, the attempt to reduce

pathological studies is no longer made in standard studies.

A number of different statistical techniques are

used to determine whether there is a significant

increase in tumors associated with exposure to the

chemical and, if so, whether there is a doseresponse relationship (83). Data are also compared

with those on tumor incidence in the NTP historical control database. The large number of

4The very high frequency of lung tumors (and also liver tumors

in female mice) in methylene chloride tests, compared with controls,

raised the possibility that the cancers reflected an acute toxic event

causing high cell turnover. If so, the number of mutations per cell

division need not be increased, but simply the number of cell divisions. Light microscopy provided no evidence for acute toxic etfects in the lung or of increased Cell turnover: more sensitive techniques will be used in the second study. It would be unlikely that

increased cell turnover would occur at the lower doses, so that an

excess of tumors would suggest a significant carcinogenic effect. The

high frequency of chemically related liver tumors in female mice

also affords an opportunity to detertine whether these tumors have

the same oncogene pattern as the background liver tumors. Such

oncogene studies may provide added information on the significance

of liver tumors.
156

these historical controls improves statistical power

in determining whether rare tumors are in fact related to a chemical under study.

Classification of Carcinogenicity

The study in one sex of one species constitutes

an “experiment. ” The NTP classifies carcinogenicity for each individual experiment. Based on

statistical and biological significance, the results

of each experiment are classified into one of five

levels of evidence for carcinogenic activity:

1.

2.

3.

4.

5.

clear evidence—a dose-related increase of

malignant neoplasms or—a combination

of benign and malignant neoplasms, or a

marked increase of benign neoplasms that

may progress to malignancy;

some evidence-the strength of the evidence

for carcinogenicity is less than for the first

category;

equivocal evidence—a marginal increase of

neoplasms that may be chemically related;

no evidence; and

inadequate study—a major quantitative or

qualitative limitation prevents interpretation

(93).

Quality Assurance

Prechronic and chronic testing, necropsy, and

histopathologic examination are performed primarily in contract laboratories. In May 1982, after testing had been transferred from NCI to NTP,

Tracer Jitco ceased to provide oversight of contractor testing and NTP assumed greater responsibility for monitoring the tests. In 1983, NTP

withdrew a draft report of carcinogenicity studies

on methylene chloride administered by gavage because of a contractor’s poor testing practices. As

a result, NTP developed stringent quality assurance

procedures (19,93). These include retrospective

data audits of each step in testing, from analysis

of the chemical to review of the histopathological sections. Contract laboratories are also visited

at least once annually and must submit monthly

progress reports. A report by the General Accounting Office in 1984 concluded that NTP’s new

auditing procedures greatly strengthened quality

control of testing (201).

Histopathological sections are examined by two

independent groups of pathologists. Although neither is blinded with regard to the dose the animal received or the gross lesions, the Chairman

of the NTP Pathology Working Group (PWG)

selects sections for additional examination by

PWG members, who are not told whether the sections come from exposed or control animals.

Review and Publication

Following a retrospective audit of all study data

and resolution of any discrepancies, a technical

report is prepared by the chemical manager. It is

first reviewed by NTP staff, and then submitted

for peer review to the Technical Reports Review

Subcommittee of the Board of Scientific Counselors. The public is informed when the results

will be considered by the Peer Review Panel in

open meeting. Since industry, labor, and academia are represented on the subcommittee, the classifications receive a full and candid critique from

the principal parties concerned. Draft reports are

made available to anyone on request.

Following approval by the Peer Review Panel,

a final technical report is printed and distributed,

usually within 9 months. When the preliminary

histopathological evidence suggests that a chemical is highly carcinogenic, the agencies represented on the NTP Executive Committee are notified before the technical report is completed, as

are manufacturers, trade associations, labor unions, public interest groups, and other groups

monitoring carcinogenicity, such as the International Agency for Research on Cancer (IARC).

Such a procedure was followed, for example, for

the inhalation studies of methylene chloride and

1,3-butadiene. The notifications stated that the

findings were preliminary.

NTP has an agreement with the National Library of Medicine to enter the results of NTP

studies in TOXLINE, a computerized database to

which the public has access, before printing and

distribution of studies’ technical reports. This will

result in wider and earlier availability of the Summary results.

The results of genetic toxicity tests are published

in peer-reviewed journals, for which there are frequently long delays between submission and publication. Results had been published in the NTP

Technical Bulletin before its publication was terminated in 1983.
157

OBSERVATIONS ON THE NTP NOMINATION

AND SELECTION PROCESS

Criteria for Nomination and Selection

Nominating sources are asked to submit a

description of the chemical and its properties and

any available information on:

1.

2.

3.

4.

5.

production, uses, occurrences, and analysis;

toxicology;

disposition and structure-activity relationships;

ongoing toxicological and environmental

studies; and

a rationale for the recommendation and suggested studies (257).

The Ad Hoc Panel charged by NTP’s Board of

Scientific Counselors to examine NTP’s testing

and evaluation program criticized the lack of emphasis on human exposure, either its magnitude

or frequency, in the process of selection (258). In

its reply to the Ad Hoc Panel, NTP maintained

that exposure was considered in selecting chemicals for tests, and that it would obtain current information from manufacturers on production volumes and exposures during production and use

(259). NTP now communicates both with manufacturers and trade associations. It also uses information on potential worker exposures from the

National Occupational Hazard Survey and the

National Occupational Exposure Survey conducted by NIOSH. The NRC report earlier cited

also emphasized the importance of considering exposure along with “suspicion of toxic activity, ”

in planning toxicity tests (138).

There are a number of problems, however, in

emphasizing exposure in this way. The first is inadequacy of information. The NRC committee

found that, of all types of information needed for

health hazard assessments, the least information

was available on exposure. For 36 chemicals in

its subsample of 100 tested chemicals “no data

were available from which the committee could

determine the extent of exposure, and, for 75 of

the substances in the subsample, no information

was available from which trends in exposure could

be estimated.”5

A second problem relates to the second point

that the NRC committee suggested should provide a basis for selecting chemicals, “suspicion of

toxic activity. ” Despite strides in understanding

the chemical substituents that may cause toxicity, great ignorance remains. Again, the original

intent of the NCI program was to learn more

about the structure-activity relationships of carcinogenicity, and this focus was carried over into

the NTP. What has become increasingly apparent, however, is the inability to predict with certainty the carcinogenicity of a chemical from its

structure. This unpredictability creates a dilemma

in setting policy for testing. On the one hand, priority could be given to chemicals whose testing

could reveal more about the relation of chemical

properties to carcinogenicity. On the other, it

could be given to chemicals for which potential

or actual human exposure (or exposure of other

components of the ecosystem) is great, or which

is suspected of being a human carcinogen. Not

all chemicals fit into both categories. (Nor is it

always possible to predict or determine exposure. )

A toxicologist with the Environmental Defense

Fund commented to OTA:

It is much more likely for a substance with

strong structural resemblance to a known carcinogen or mutagen to be nominated for testing,

rather than a compound for which there is quasiepidemiologic reason to suspect carcinogenicity

(186).

‘The NRC report gave several reasons for the lack of exposure

data: 1 ) There are few reporting requirements. “Even data on production volumes of substances and numbers of people involved in

manufacture, distribution, use, and waste disposal are limited. ” 2)

There is little incentive for voluntary reporting. 3) Monitoring for

compliance of standards focuses on specific substances, few of which

were included in its subsample. “Furthermore, data collected for compliance monitoring may be of limited value in evaluating population exposures. ” 4) “Little is known about physical processes and

procedures that affect the exposure potential for uses other than those

intended. For example, the intensity of occupational exposure is

strongly influenced by the choice of process and control equipment,

and the intensity of environmental exposure is strongly influenced

by the selection of waste-disposal technique, chemical reactivity,

and degree of biodegradability ’’(l38).
158

A third problem in emphasizing exposure is

duplication of NTP efforts with efforts by manufacturers or processors required by regulatory

agencies. Section 4 of TSCA established ITC to

“designate” or “recommend” chemicals in

commerce, as defined by TSCA, to be tested for

certain health or environmental effects. EPA can

then require manufacturers and processors to test

these chemicals. (See ch. 3.) As mentioned earlier,

several chemicals recommended for industry testing under TSCA were under test or scheduled for

test by NTP in 1980 (117).

At the suggestion of EPA officials, who were

concerned about NTP’s activities overlapping with

those of TSCA, NTP established eight “chemical

selection principles, “ drafted in 1979 by EPA staff

members (table 4-2). The introduction to the principles recognizes that industry has responsibility

for testing chemicals under the authority of agencies created by Congress, although principle 8 indicates that there may be special situations in

which NTP would test chemicals that “have potential for large-scale and/or intense human exposure, ” even if industry could be required to test

them. Principle 3 recognizes improving the understanding of structure-activity relationships as a

criterion for selection. Principle 5, permitting testing of previously tested chemicals “to cross-compare testing methods, ” follows from NTP’s goal

of developing and validating new tests. The remaining principles implicitly recognize the importance of human exposure as a basis for selection,

but for those chemicals that industry cannot be

required to test. These include chemicals in the

environment not associated with commercial activities (principle 1), old chemicals whose manufacturers derive “too little revenue to support an

adequate testing program” (principle 6), and

groups of chemicals manufactured by different

companies for which the companies “probably

cannot be required” to test (principle 7).

Duplication of NTP and regulatory agency testing is also avoided through liaison between NTP

and ITC; the NIEHS is a voting member of ITC,

and EPA, under whose authority ITC operates,

is represented on CEC. Before conducting a

detailed review, ITC asks NTP for information.

At the present time, ITC and NTP use the same

contractor, Dynamac, to prepare the documentable 4-2.—NTP Chemical Selection Principlesa

1. Chemicals found in the environment that are not closely

associated with commercial activities (1 1);

2. Desirable substitutes for existing chemicals, particularly

therapeutic agents, that might not be developed or tested

without Federal involvement (l);

3. Chemicals that should be tested to improve scientific

understanding of structure-activity relationships and thereby assist in defining groups of commercial chemicals that

should be tested by industry (91);

4. Certain chemicals tested by industry, or by others, the additional testing of which by the Federal Government is

justified to verify the results (27);

5. Previously tested chemicals for which other testing is

desirable to cross-compare testing methods (8);

6. “Old chemicals” with the potential for significant human

exposure which are of social importance but which generate too little revenue to support an adequate testing program (some of these may be “grandfathered” under FDA

laws) (15);

7. Two or more chemicals together, when combined human

exposure occurs (such testing probably cannot be required

of industry if the products of different companies are involved) (l); and

8. In special situations, as determined by the Executive Committee, marketed chemicals which have potential for largescale and/or intense human exposure, even if it may be possible to require industry to perform the testing (39).

aNu~b~~~ in pa~~”tfleses indicate the number of ti(TW3 the Princi Ple was used

to support a CEC recommendation for testing In animals.

SOURCE: National Toxicology Program

tation for their reviews (18). Liaison reduces the

likelihood of duplicate testing under the NTP principle 8. ITC has nominated chemicals for NTP

testing to decide whether to recommend chemicals for more extensive industry testing (principle 3). Most chemicals nominated by ITC have

been for short-term genetic toxicology testing (see

table 4-3).

In table 4-2, the number of times CEC cited each

principle to support a recommendation for extensive animal testing between fiscal year 1981 and

1986 is shown in parentheses following each principle for 123 chemicals; more than 1 or even 2

principles were used to justify the testing of some

chemicals. Of the 193 citations of principles, the

most frequent was of principle 3 (referring to

structure-activity relationships), a total of 91

times. Although principle 7, focusing on combinations of chemicals, has only been invoked once,

NTP has other initiatives under way on mixtures

that are not part of the chemical nomination and

selection process. These include a contract with

the National Academy of Sciences to develop
159

Table 4.3.—Source of Nomination of Chemicals for Mutagenicity and Bioassay Testing by NTP by Year

Year of nomination

1979 1980 1981 1982 1983 1984 1985 1986

Source Mut Bio Mut Bio Mut Bio Mut Bio Mut Bio Mut Bio Mut Bio Mut Bio

Government:

CPSC . . . . . . . . . . . . . . . . l

a

EPA . . . . . . . . . . . . . . . . . 1

34b 19 28 1

FDA . . . . . . . . . . . . . . . . . 1 1 7 5

c

ITC . . . . . . . . . . . . . . . . . . 2 5 1 1 1 1

NCI . . . . . . . . . . . . . . . . . . 176 56 48 14 6 4 15 d 5 24’

NIEHS . . . . . . . . . . . . . . . 136 195 62 30 15 121 3 6

N!OSH . . . . . . . . . . . . . . . 92 2 4

OSHA . . . . . . . . . . . . . . . . 1 1

State agencies . . . . . . . . 1 1 5 1

Nongoverment:

Individuals . . . . . . . . . . . . 1 7 3 4121 3

Industry . . . . . . . . . . . . . . 1

National Academy

of Sciences. , , . . . . . . 2

Professional

associations . . . . . . . . 1

Unions . . . . . . . . . . . . . . . ———————— 9 5 —1 1

Totals . . . . . . . . . . . . . . NA 303f 3009 60h 228 50 197 32 108 14 50 58 122 33 6 44

aZ.bUtOXYethanOl also nominated by UAW international Union; only shown under CpSC.

bAlkylepoxides nominated jointly by EPAand NIEHS; only shown under EpA.

cfnc[udes 4 benzodlazeplnes nominated by NIEHS in 1~.

dlncludes 8 submitted for reconsideration and one (Oxymetholone) also nominated by NIEHS (shown only under NCI).

elncludes 6 resubmissions by NCI and one nominated by NIEHS in 1984.

fNTp could not provide information on the nominators for bioassay testing for fiscal years 1979, 1980, and 1981 other than frOm NCI,

gNominatlons came from EPA, NIOSH and FDA (NCTR). Breakdown not available. The EPA nominations were submitted in reSPOflSe to ITC designations of chemical

classes for possible industry-required testing and to aid In the pre-manufacture notification program.

‘Added in.

KEY: Mut —mutagenicity tests only, Bio—bioassay (extensive testing in animals); NA—not available; EPA—Environmental Protection Agency, FDA—Food and

Drug Administration, ITC—interagency Testing Committee; NC1—National Cancer Institute; NIEHS—National Institute of Environmental Health Sciences,

NIOSH —National Institute for Occupational Safety and Health; OSHA—Occupational Safety and Health Administration

NOTE: Data on sources of nominations for mutagenicity tests is complete only after 1981. In prior years, blank spaces mean that data was not available, not that nominations from the particular source were not made. For the same reason, the same applies to blank spaces for bioassay nominations prtor to 1982

SOURCE” National Toxicology Program

guidelines for studying complex mixtures; chemical disposition studies of well-defined mixtures;

and a Superfund-sponsored effort to characterize the toxic potential of chemicals and mixtures

found at waste dump sites.’

OTA obtained from NTP a list of the chemicals for which principle 3 was invoked to recommend either genetic toxicology or animal studies.

Eighty-eight chemicals on the list were unequivocally positive in one or more short-term genetic

toxicology tests, but have not been tested further

by NTP. OTA asked ITC and the EPA Office of

Toxic Substances whether they had required, or

considered requiring, industry to test any of these

chemicals in accord with principle 3. Of the 77

chemicals that were in the TSCA inventory, ITC

b

In general, NTP strives to test single, pure chemicals. Seldom,

however, are humans exposed to isolated pure chemicals.

has considered 61 chemicals and conducted detailed reviews on 19 that might present the greatest

human health hazards. Of the 19, it has deferred

further consideration of 12 and recommended 7

for testing to EPA. Deferral is based on low production volumes, low exposure potential, or adequate knowledge of closely related chemicals.

Three of the seven recommended chemicals were

tested before NTP was created. In 1983 EPA issued an Advance Notice of Proposed Rule Making on one of these, bisphenol A diglycidyl ether

(320). Although EPA noted the mutagenicity of

several glycidyl compounds, it did not cite NTP

studies among its sources. EPA has also issued a

Notice of Proposed Rule Making on two of the

other chemicals recommended by ITC after NTP

was established, namely, meta- and ortho-phenylenediamine (321). The mutagenicity of these compounds was reported before the creation of NTP,

and neither the ITC recommendation nor the pro-
160

posed rule cites the NTP genetic toxicology results. The other two reports on chemicals ITC recommended for testing do not mention a positive

NTP mutagenicity result. Of the 12 chemicals

whose consideration ITC deferred, 4 were reviewed before NTP was organized. Five of the remaining eight (including four xylidines) mention

a positive NTP genetic toxicology result (18).

Thus, a small proportion of the chemicals studied under principle 3 that have positive genetic

toxicology results have been recommended or proposed for industry testing. Many of the chemicals studied under principle 3 were of little interest to ITC or EPA, however, usually because of

low production or low human exposure potential. An NTP official told OTA that many of the

chemicals selected under principle 3 represented

chemical classes nominated solely for Salmonella

testing, to examine the effects of structural modifications on the genotoxic potential of the class and

to ascertain the usefulness and predictivity of the

assay for the different classes of chemicals. In

these cases, the principle was not used to propose

chemical candidates for further industry testing

(26). A rewording of principle 3, or perhaps dividing it into two principles, one focusing on structure-activity relationships and the other on defining groups of chemicals for industry testing, might

clarify the situation.

Number, Source, and Disposition of

Nominated Chemicals

Table 4-3 indicates the sources of nominations

submitted each year to NTP for mutagenicity testing and bioassays (animal testing). From 1980 to

1986, 1,011 chemicals have been nominated only

for mutagenicity testing. There has been a steady

downward trend in the number nominated for

mutagenicity tests, except in 1985. In that year,

NIEHS nominated 121 dump site chemicals. Since

1981, 54 percent of all nominations for mutagenicity tests have been made by NIEHS; its nomination of fewer chemicals accounts for most of

the decline. In 1981 and 1982, most of the NIEHS

nominations requested examining structure-activity relations, which has not been the case more

recently.

A total of 594 chemicals have been nominated

for bioassays from 1979 to 1986. In January 1979,

shortly after NTP was created, all participating

agencies were asked for their nominations and

several hundred were received. Thereafter the

numbers were considerably smaller. Since 1980,

the number of chemicals nominated for animal

testing has fluctuated between 14 and 60 per year

without any discernible trend.

Of the 942 nominations for all types of testing

between 1981 and 1986, 42 came from nongovernment sources; unions nominated chemicals most

frequently, a total of 16.

As a result of positive mutagenicity tests, some

chemicals were nominated for more extensive testing. New information about a chemical can also

lead to renomination and recommendations for

additional testing. For instance, methyl isocyanate

was originally selected only for genetic toxicology tests, because extended human exposure was

considered unlikely (26). After the disaster at the

Union Carbide plant in Bhopal, India, in which

methyl isocyanate was accidentally released, studies on the delayed effects of a single exposure were

undertaken (257).

Of 186 chemicals nominated for more than

mutagenicity testing and reviewed by CEC between 1981 and 1986, 114 were recommended for

testing (61 percent). CEC recommended animal

testing of 59 percent of chemicals nominated by

government agencies and of 72 percent of those

nominated by nongovernment sources. It did not

recommend testing of more than half of the chemicals nominated by FDA and about half of the

chemicals nominated by NIEHS. In 1986, CEC did

not recommend 53 percent of chemicals for testing, a greater proportion than ever before.

Examination of the data provided by NTP indicated the initial response of the Board of Scientific Counselors to 164 chemicals acted on by

CEC (table 4-4). Regarding 130 chemicals (79 percent), CEC and the Board agreed in their recommendations. For eight (5 percent), CEC recommended testing and the Board recommended that

testing not be done. For four (2.4 percent), CEC

did not recommend testing while the Board recommended testing. These four chemicals were all

reconsidered by the Board after 1984.
161

The number of chemicals selected for testing is

consistent with the NTP budget. Because of budgetary cutbacks in fiscal year 1986, priorities were

recentl y set for chemicals selected for testing, but

for which studies had not yet begun. Chemicals

given low priority may not be tested unless new

information about their toxicities or exposures

raises their rank or additional funding becomes

available.

Duration of Testing Process Stages

OTA obtained information from NTP on the

time from nomination to NTP Executive Committee action for every chemical nominated for bioassay reviewed by CEC in fiscal year 1981 or

1982 (table 4-5). For those chemicals in this “cohort” whose bioassays the Executive Committee

approved, OTA obtained the time from Executive Committee action to testing status as of January 1987 (table 4-6). For most chemicals, it took

over 2 years from the time of nomination to action by the Executive Committee. It took approximately half of this time before CEC acted. There

times do not appear to have decreased appreciably in more recent years. Action by the Board of

Scientific Counselors added another 3 to 8

months. For 7 chemicals for which CEC recommended no testing and for 13 for which it recommended testing (see table 4-4) the Board deferred

action; it also deferred action on one chemical as

had CEC. These deferrals add further time. Of

these 21 chemicals, 6 have been rereviewed by the

Board. In each case, on rereview the Board agreed

with CEC’s original recommendation. It should

be recalled that Board review is omitted for any

regulatory agency’s priority chemical.

No chemical approved for animal testing in either fiscal year 1981 or 1982 has yet passed

through the entire process. Of the 30 chemicals

approved for testing in those 2 years, only four

have reached the stage of chronic testing. Twentytwo are being tested in the prechronic phase. Testing of four has been deferred or withdrawn because of budget constraints. Of these four chemicals, one presented unusual technical difficulties

(benzoyl chloride), one was no longer produced

(m-chloroaniline), one had been tested for carcinogenicity by industry and found by NTP disposition studies not to be absorbed from the gasTable 4-4.—initial Response of Board of Scientific

Counselors to Actions of the Chemical Evaluation

Committee (CEC) on 164 Chemicals,

Fiscal Year 1982 - Fiscal Year 1986

Board’s recommendation

(number of chemicals)

CEC action No test Defer Test

No test . . . . . . . . . . . . 35 7 4

Defer. . . . . . . . . . . . . . 0 1 1

Test. . . . . . . . . . . . . . . 8 13 95

SOURCE: National Toxicology Program,

trointestinal tract (CI Vat Blue No. 1), and one

was found not to metabolize to the suspected carcinogen (1,3 -dichloro-5,5-dimethylhydantoin).

Considering the time to develop protocols, announce, accept, and negotiate contracts for testing, perform chemical disposition studies to determine the extent of absorption through various

administration routes, and conduct prechronic

studies, it becomes clear that the 2 years of the

chronic phase itself greatly underrepresents the

total time needed for carcinogenicity bioassays.

Table 4-7 lists the five priority chemicals nominated by the regulatory agencies for “fast track”

analysis. This process took no longer than 5

months for any of the chemicals from the time

of nomination as an agency priority chemical to

NTP Executive Committee selection, a time shorter

than for any nonpriority chemical by 3 months.

The shorter time is due to rapid preparation of

the executive summaries by NTP, rather than by

a contractor, and to omitting consideration by the

Board of Scientific Counselors. Although none of

the agency priority chemicals have reached the

stage of chronic testing yet, the earliest was

selected in 1984. Thus, while the early processing for the chemicals has been prompt, too little

time has elapsed to conclude whether their testing will be completed more rapidly.

Case Study in Nomination and

Selection: the Benzodiazepines

From documents obtained from NTP and interviews with some of those involved, OTA tracked

the nomination and selection of five widely used

benzodiazepine (BDZ) drugs that were recently

approved conditionally for NTP testing. OTA

cannot say whether the process has been similar
162

Table 4-5.—Time (in months) From Nomination of Chemicals Considered by the Chemical Evaluation Committee

(CEC) in Fiscal Year 1981 and Fiscal Year 1982 to Intermediate and Final Points in the

Process of Approval for Testing by NTP

From time of nomination to:

CEC recommendation Action by Board of Scientific Action by Executive

(months) Counselors (months) Committee (months)

Year of CEC review <13 13-18 19-24 <13 13-18 19-24 >24 <19 19-24 25-30 >3 0

Fiscal year 1981:

Number of chemicals . . . . . . . 33 12 1 9 23 14 0 1 3 19 0

Fiscal year 1982:

Number of chemicals. . . . . . . 28 18 1 0 16 30 1 0 0 4 8

a

23 nominated chemicals Were not recommended for prechronic and/or carcinogen icity testing and were not, therefore, referred to the Executive Committee.

b35 nominated chemicals were not recommended for prechronic and/or carcinogenicity testing and were not, therefore, referred to the Executive Committee.

SOURCE: National Toxicology Program.

Table 4.6.—Status of Chemicals Approved for Testing by the NTP Executive Committee

in Fiscal Year 1981 or Fiscal Year 1982 (status as of January 1987)

Prechronic phase Chronic phase

Year of executive Deferred or TDRCa Contract Testing TDRCa Contract Necropsy

committee approval withdrawn approval awarded initiated review awarded complete-d

Fiscal year 1981:

Number of chemicals. . . . . . . . 4

b

2 0 8 0 3

C

1

Fiscal year 1982:

Number of chemicals. . . . . . . . 0 2 1 8 1 0 0

aToxicology Design Review cornrnmee.

bThree chemicals were deferred in July, l=because of budget constraints,one chemical was withdrawn by the Executive cOf71111ittW3 in October, 1984.

cchronic te5ting initiated for one chemical in December 1~. Contract awards anticipated for the other two by March, 1987,

SOURCE: National Toxicology Program.

Table 4-7.—History of Agency Priority Chemicals (status as of April 1987)

NTP

Nominating Date of priority Executive Committee

Chemical agency nomination selection date Status, April 1987

D&C Yellow No. 11 . . . . FDA 9127183

Gallium arsenidea . . . . . NIOSH 7/16/84

2-Butoxyethanol . . . . . . . CPSC 9/27/84

t-Butyl-hydroquinone . . . FDA 7129185

Styrene . . . . . . . . . . . . . . NIOSH 12/13/85

aOriginally nominated Dec. 8, 1983.

SOURCE National Toxicology Program.

for other chemicals. Questions on studies of

classes of chemicals and on industry’s role in testing were also raised in NTP’s consideration of

these drugs for testing.

Four of the BDZs that were nominated are frequently used to relieve anxiety: diazepam (Valium), chlordiazepoxide (Librium) and clorazepate

(Tranxene), and oxazepam (Serax). The fifth,

flurazepam (Dalmane), is used as a hypnotic (sleep

inducer). The first three are metabolized to oxazepam. These drugs were marketed prior to 1968,

when FDA began to require carcinogenicity test1127184 Prechronic testing

8131184 Contracted for prechronic testing

3/07/85 Out for bid (prechronic)

12/19/85 Out for bid (prechronic)

2/13/86 Protocol for prechonic in preparation

ing. They are still extensively used, with over 2.5

million prescriptions written for the least frequently prescribed (oxazepam), and over 25 million for the most frequently prescribed (diazepam)

in 1983. Diazepam ranked third in “new prescriptions” in 1985 and fourth for “new and refilled”

prescriptions. 7

7This and the following information on toxicity studies was obtained from the draft executive summaries submitted by Dynamac

to NTP on October 28, 1986. Citations are to the original sources.
163

In 1980, an NTP senior toxicologist, Dr. James

Huff, sent a memo to the Deputy Director of

NTP, in which he suggested that diazepam, chlordiazepoxide, and oxazepam “be tested first in the

Genetic Toxicology Component and at the same

time be nominated for long-term carcinogenesis

bioassay, ” His concern was based on a report of

liver cell adenomas in mice receiving oxazepam.

Huff considered the study inadequate because of

the small number of animals used and the short

duration (94). No nomination was submitted to

the NTP office responsible for processing nominations. In 1984 Huff sent to the Director of Toxicology Research and Testing Program and the assistant to the director of NTP, who are responsible

for processing nominations, a new report of liver

tumors in male mice administered large doses of

another BDZ, ripazepam, together with a copy

of his earlier memo. Shortly thereafter, the three,

as well as clorazepate, were nominated for study

by NIEHS (25).

The FDA joined in the nomination on March

31, 1986, after NTP requested that it provide unpublished data on toxicologic testing of the drugs

that could be included in the executive summaries

(26), At that time, FDA also nominated flurazepam for study. FDA based its nominations on

●

●

●

●

the extensive use of these drugs,

the inadequacy or absence of carcinogenicity studies on them,

an increased incidence of liver tumors in mice

and benign thyroid tumors in rats given some

newer BDZs that were required to undergo

extensive carcinogenicity testing prior to marketing, 8 and

the need to determine whether the types of

tumors observed in the newer drugs were

characteristic effects of the class of BDZs or

specific for each chemical (361).

In fact, FDA has not approved new drug applications for some of the newer BDZs because of

the finding of tumors in animals (193).

The nominations were not reviewed by CEC

until September 1986, after their nomination by

FDA. The delay between the time of initial nomination and CEC review was due largely to a backlog that had accumulated while NTP was attempting to get a new contractor to prepare the

summaries for the CEC. CEC recommended the

drugs for bioassay (prechronic and chronic testing two with high priority (diazepam and flurazepam) and one (oxazepam) with moderately high

priority. (The recommendations were based on

principles 3 and 4; see table 4-2. ) It did not recommend clorazepate and chlordiazepoxide for

testing because the three related BDZs were recommended. The summaries prepared for CEC do

not make clear, however, that oxazepam is the

major metabolize of both drugs. 9 Additional reasons for not recommending these drugs were that

previous chronic studies indicated minimal toxicity of clorazepate, although the reviewer noted

that “no carcinogenicity studies were done, ” and

that the use of chlordiazepoxide “was declining”

(261).

The Board of Scientific Counselors reviewed the

five BDZs in November 1986. One of the questions raised by a counselor at the meeting was

whether the results for one drug could be extrapolated to others that have the same metabolize.

The answer given by NTP staff was “no. ” In fact,

one of the problems of doing “class” studies is that

when one or more members of a class is found

to be carcinogenic, a new member of the class,

which may differ by only a single substituent,

must be tested in order to establish its carcinogenicity. It is for this reason that NTP has tested

several derivatives of benzidine and several phthalates. The difficulty arises because of the imperfect ability to predict carcinogenicity from

structure.

‘Data in the summary prepared for CEC does not indicate oxazepam in the blood or urine following chlordiazepoxide administration to human volunteers. The summary on clorazepate does not

indicate the urinary metabohtes following administration of the drug.

Desmethyldiazepam, an immediate precursor of oxazepam, “is the

‘The 1968 FDA guidelines for carcinogenicity testing called for major metabolize of clorazepate in the blood. ” Diazepam is also conan 18-month study in rats only. Manufacturers now submit data verted to desmethyldiazepam. In one study, only 16 percent of the

on both sexes of rats and mice in their new drug applications, al- administered dose was excreted as a conjugate of oxazepam, the mathough there is no formal requirement for them to do SO. jor form of oxazepam excretion.
164

The Board voted unanimously to recommend

that NTP test all five BDZs subject to an extensive review of existing studies “to determine

sex/species combination in which to test individual chemicals” (260). The NTP Executive Committee accepted the recommendation on December 18, 1986, giving highest priority to the three

drugs originally recommended for testing by the

CEC. Because of budgetary constraints, it is not

yet clear how many of the five drugs will be tested

in animals.

The only BDZ selected by NTP for genetic toxicology testing prior to review by CEC was diazepam, and this occurred in December 1985. Following action of the CEC in September 1986, NTP

genetic toxicology staff added flurazepam and oxazepam. To OTA’s knowledge these tests have not

yet been conducted. When the CEC was considering the BDZs the question was asked why FDA

did not require industry to test the compounds.

Although the patents on the older BDZs had expired, FDA could still have required companies

to test drugs that they are marketing. (They did

get Wyeth and Hoffmann-LaRoche to perform

carcinogenicity studies in rats on oxazepam and

diazepam, respectively, after they had been marketed but while they were still under patent. In

view of the finding on the newer BDZs, FDA is

now interested in mouse studies. ) FDA apparently

chose not to require such testing in 1986 for at

least two reasons. First, they would have to get

several companies to collaborate in carrying out

a suitable protocol; since the drugs were no longer

under patent, several companies were marketing

each BDZ. (There is precedent, however, for

FDA’s requiring manufacturers to agree on a common protocol and to contribute to testing of pharmaceutical agents (193). ) Second, FDA had limited leverage on the companies. Without evidence

of these drugs’ human carcinogenicity, regardless

of their widespread use, it is not likely that FDA

would prevail if it sought to remove the drugs

from the market. FDA could require that the drug

label state that the drug has not been tested adequately for carcinogenicity (if that was the case),

but an FDA spokesperson doubted that most clinicians would be affected greatly by such a statement (193).

MUTAGENICITY TESTING: CORRELATION

WITH ANIMAL CARCINOGENICITY

The initiation of cancer may involve the mutation of particular nucleotides that form the backbone of DNA. Evidence that chemicals cause mutation or combine with DNA or affect its function

can be obtained rapidly by a variety of in vitro

and in vivo methods. The recent discovery that

certain genes (proto-oncogenes) can be converted

to oncogenes by known chemical carcinogens

(chemicals associated with the presence of tumors)

extends this work and promises better short-term

methods to determine carcinogenicity (115). Work

on developing such methods is being conducted

at NTP and NCTR.

At the present time, the “Ames” test, which

measures mutant frequencies in one or more

strains of Salmonella bacteria, is the most extensively used test for genetic toxicity. At NTP, such

results are considered in deciding how to proceed

with bioassays for carcinogenicity in rats and

mice. NTP results of Salmonella mutagenesis tests

have been published on 775 chemicals. These tests

were performed in one or more of three contract

laboratories. The laboratories did not know the

identity of the chemicals. Multiple doses were each

tested in triplicate. Positive and negative control

chemicals (that is, known mutagens and known

nonmutagens) were also used in each experiment.

Reproducibility within and between laboratories

was documented in most cases. Of the 775 chemicals tested, 194 (25 percent) were clearly mutagenic, and 49 (6 percent) gave questionable results

(in one laboratory) or different results in different laboratories. The remaining 532 (69 percent)

were negative (87,133,367).

At the request of the Board of Scientific Counselors, NTP compared the results of short-term

tests for genetic toxicity with those of animal tests
165

for carcinogenicity (194). It performed Salmonella

mutagenicity tests on 44 chemicals that were carcinogenic in NTP tests in at least 1 animal experiment (an experiment is defined as the test in 1

sex of 1 species), on 20 chemicals that were negative in all animal experiments (both sexes of 2 species, usually mice and rats), and on 9 chemicals

that gave equivocal results in the animal studies.

Except for 10 chemicals that could not be tested

for technical reasons, these 73 chemicals were all

of those tested in NTP long-term studies of carcinogenicity in which the animals were sacrificed

in 1977 or later and on which the conclusions had

been approved by peer review before 1985. ’0

Counting the equivocal animal tests as negative,

20 of the 24 chemicals that were mutagenic in the

Salmonella test had proved to be carcinogenic in

animals (83 percent, predictive value positive

(PVP)), and 25 of the 49 chemicals that were nonmutagenic had proved to be noncarcinogenic (51

percent, predictive value negative (PVN)). The

chance that an animal carcinogen would give a

positive Salmonella test (the test’s sensitivity) was

45 percent, and the chance that a noncarcinogen

would give a negative test (the test’s specificity)

was 86 percent. There is some increase in the PVN

when the following factors are taken into consideration: carcinogenic potency (the lowest dose

producing tumors in animals), ” malignancy of

animal tumors, number of animal experiments

that gave positive results, number of organ sites

with tumors, and exclusion of liver tumors. But

there are decreases in the PVP when each of these

factors is considered. With 224 chemicals in the

entire NCI-NTP database on which Salmonella

and carcinogenicity testing had been done, the

PVP was 69 percent; the PVN, 45 percent; the sensitivity, 54 percent; and the specificity, 70 percent. The range of concordance—agreement between Salmonella and animal test results (positive

10This and the following information was obtained at the NTP

Board of Counselors meeting, November 25, 1986.

11This was not true for all chemicals. For instance, very low doses

of 2,3,7,8, -tetrachlorodibenzo-p-dioxin (“dioxin”) and polybrominated biphenyl (PBB) mixtures were positive in all animal experiments, as was reserpine in three of four animal experiments. Yet

all three chemicals gave negative results in the Salmonella and other

tests for genetic toxicity (desuibed below). Dioxin and PBBs are

known to act as tumor promoters under certain circumstances.

and positive, negative and negative) —when each

of these factors is examined separately varies between 62 and 74 percent.

NTP performs additional short-term tests on

most chemicals in the genetic toxicology program.

These include the mouse lymphoma (ML) mutagenesis assay, tests for chromosome aberrations

(CA) in Chinese hamster ovary (CHO) cells, and

sister chromatid exchanges (SCE) in CHO cells.

These tests are all performed in vitro. NTP also

examined the predictivity of these tests for animal carcinogenicity alone and in combination

with each other or the Salmonella test. The PVP

of each was less than the Salmonella test (ML 66

percent, CA 73 percent, and SCE 67 percent), and

the PVN was about the same (50 to 52 percent).

There was no combination of two, three or all

of these tests that gave much higher concordance

with animal test results than the Salmonella test

alone (66 percent v. 62 percent). Nor were chemicals that caused positive responses at lower doses

in any of these genetic tests more likely to be carcinogenic in animal bioassays than those for

which higher doses were needed. Nor did a sequential approach—in which chemicals negative

in one genetic test were then subject to the other

three short-term tests—significantly improve the

ability to distinguish animal carcinogens from

noncarcinogens. NTP found no combination of

tests or other test to represent a substantial improvement over the Salmonella test.

NTP performed 2 other short-term genetic tests

on some of the 73 chemicals: the test for unscheduled DNA synthesis in rat primary hepatocytes

on 44, and the sex-linked recessive lethal assay

in Drosophila on 27. The specificity and PVP were

both high (with a specificity of 0.93 and 1.0 respectively, and a PVP of 0.86 and 1.0 respectively), but sensitivity and PVN were much lower

for these than for the other tests.

Some short-term tests involving mammalian

cells can be conducted in vivo. The chemical is

administered to the animal, and tests are performed on cells obtained either from liver or bone

marrow. In vivo tests for unscheduled DNA synthesis in rodent liver cells were generally negative for animal carcinogens and noncarcinogens,

in tests of 16 chemicals. Two short-term tests, SCE
166

and CA, were performed on the same 16 chemicals in vivo on mouse bone marrow cells. Of the

eight that were known animal carcinogens, all

gave positive SCE results in vitro; only six gave

positive results in vivo. Seven of the animal noncarcinogens gave positive SCES in vitro; only four

gave positive results in vivo. The carcinogens also

gave fewer positive in vivo CA responses than

positive responses in vitro (four compared to six);

the noncarcinogens gave fewer positive in vivo

responses (one compared to four in vitro). When

in vivo tests on mouse bone marrow were performed on seven carcinogen-noncarcinogen pairs

of structural analogs, the CA test correctly identified the carcinogenic member of five of the chemicals without giving any false positives. In the SCE

test, four of the carcinogens were positive, but

five of the noncarcinogens were also positive.

NTP will perform in vivo assays of additional

chemicals. It will also incorporate them into

prechronic tests. It is possible that nonmutagenic

chemicals do not act as initiators, that is, do not

cause mutations in DNA, but instead act as promoters, whose mechanism of action is poorly

understood. Animals administered promoters

sometimes show regression of preneoplastic or

neoplastic lesions after the administration of the

chemical is stopped. For some chemicals selected

for carcinogenicity testing, but which are negative in short-term tests, NTP conducts “stop”

studies, in which administration is discontinued

in some animals but not in others (115); regression or absence of tumors in the first set, but not

in the second would be consistent with the observations made so far for several promoters.

Although the results of these studies show a fair

degree of consistency among the different tests,

suggesting that not all studies need be performed,

they fail to show very good agreement with the

results of animal testing. In discussing the results,

NTP staff concluded that the short-term tests

could not be used as surrogates for long-term rodent studies, but could be helpful in assessing carcinogenic potential (260).

RELATION OF CHEMICAL CARCINOGENICITY

IN ANIMALS TO CANCER IN HUMANS

IARC investigators recently compiled data on

the ability of animal tests to predict that a chemical is a human carcinogen.

Of 30 exposures (to chemicals) for which there

is sufficient evidence of carcinogenicity to humans, the animal data provide sufficient evidence

for 19. . . limited evidence for seven . . . and

inadequate evidence or no data for four . . . Of

the 14 exposures for which there is limited evidence of carcinogenicity to humans, the experimental data provide sufficient evidence for eight

. . . limited evidence for three , . . and inadequate evidence or no data for three.

. . . The four exposures for which there is

sufficient evidence of carcinogenicity to humans

that have not been adequately tested in experimental animals are: certain combined chemotherapy regimens including MOPP (mechlorethamine [nitrogen mustard] oncovine [vincristine],

procarbazine, prednisone), conjugated oestrogens, smokeless tobacco products and treosulphan. However, for some individual components

of MOPP—nitrogen mustard and procarbazine

—there is sufficient evidence of carcinogenicity

in experimental animals . . . Further, it is reasonable to believe that conjugated oestrogens

would react similarly to other oestrogens in experimental animals . . .; for some oestrogens

there is sufficient evidence of carcinogenicity to

animals (360).

For 37 of the 44 chemicals considered to be carcinogenic in humans, there was evidence of carcinogenicity in animals; in these cases, the evidence was “sufficient” for 27 and “limited” for

10. ’2 (The remaining seven chemicals were not

studied adequately. ) Further strengthening this

association was the finding that for every chemi12IARC’S definition of “sufficient evidence” in animals includes

increased incidence of malignant tumors in multiple species or strains.

The definition of “limited evidence” includes studies involving a single

species or strain, inadequate dosage levels or period of followup,

too few animals, and high rate of spontaneous tumors.
167

cal supported by sufficient evidence of carcinogenicity for both humans and animals, the same organ was involved in both; the types of tumor were

often identical or similar. Some chemicals that

subsequently proved to be human carcinogens

were first demonstrated to be carcinogens in experimental animals (4-aminobiphenyl, diethylstilbesterol, melphalan, methoxsalen with ultraviolet A, mustard gas, and vinyl chloride).

It does not follow from these studies that all

chemicals carcinogenic in animals will prove to

SUMMARY

The establishment of NTP has improved coordination of testing within the government. NTP

performs a valuable role in developing and evaluating new tests. It continues to elucidate structureactivity relationships in chemical carcinogenesis.

In most cases, NTP’s process of evaluating

nominated chemicals gathers available information to permit informed decisions on selection. It

is not clear that the chemicals to which humans

are significantly exposed are being selected adequately, in part because relatively few chemicals

are nominated. NTP does not have direct control

of nominations, other than by publishing information on the nominations process. It does consider human exposures in recommending chemicals for study.

Regardless of whether the chemicals that pose

the greatest threat to humans are being nominated, more chemicals are nominated than can be

tested given current budgets. It is possible that industry could perform more tests, as the BDZ case

study suggests. There is little evidence to suggest

that chemicals tested under NTP to “assist in

defining groups of commercial chemicals that

should be tested by industry” (see table 4-2, principle 3) are subsequently being tested by industry.

The time from nomination to selection is over

2 years for most chemicals. This time could be

shorter. Whether the testing process itself can be

shortened is problematic. The performance of

be carcinogenic in humans. It would be helpful

to demonstrate that chemicals that are not carcinogenic in humans are also noncarcinogenic in

animals. This would be an expensive undertaking.

Moreover, no universally accepted list of human

noncarcinogens exists. Although FDA requires

that all new drugs for long-term or widespread

use be tested, most other chemicals are selected

for testing because it is suspected they cause cancer in humans.

chemical disposition and prechronic tests is necessary, and eliminating them would reduce the validity of the chronic bioassays. Testing had been

completed by January 1987 on only one of the

chemicals selected in fiscal year 1981 and 1982.

Developing protocols, awarding contracts, and

performing chemical disposition and prechronic

and chronic tests takes at least 5 years; the evaluation of organs and microscopic sections adds at

least an additional year; and preparation of the

report, review, and publication add still more

time. The time required is so intrinsically long that

some chemicals presenting significant exposures

may no longer do so by the time testing is completed. There should be a mechanism by which

NTP is promptly informed of changes in the production status of chemicals, or of the substitution

of analogs, so it can modify testing schedules and

protocols accordingly. This aim may be accomplished to some extent by NTP’s announcement

of the completion of prechronic studies with a request for submission of relevant data. Chemical

managers also attempt to obtain data on current

production levels.

It is a grave oversimplification to maintain that

animal testing takes 2 years. The current research

by NTP and NCTR toward finding better biological markers of carcinogenicity may lead to better and more rapid means of detecting carcinogens in both humans and animals.
Chapter 5

Agency Responses to the Annual

Report on Carcinogens and

NCI/NTP Test Results
—. . —

CONTENTS

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....171

The Annual Report on Carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......171

History of the Annual Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........171

Development of the Annual Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...172

Contents of the Annual Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..,.....173

Listed Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..............173

NCI/NTP Chemical Test Results . . . . . . . . . . . ...............................174

Classification of Test Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........174

OTA Grouping of Test Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......174

OTA Analysis of Actions, Exposures, and Agency Jurisdictions. . .............175

Agencies and Programs Analyzed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..175

Determining Agency Actions on Annual Report Chemicals . ................176

Determining Agency Actions on NCI/NTP-Tested Chemicals. . .............176

Exposure Information.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............176

Regulatory Jurisdictions . . . . . . . . . . . . . . . . . . . . . ...........................177

Review of OTA Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........178

Results of OTA Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............178

FDA Actions on Foods and Cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ...178

FDA Actions on Human Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........181

FDA Actions on Animal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......182

OSHA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............182

NIOSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........................184

CPSC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..184

EPA Actions Under the Clean Air Act.... . ..............................185

EPA Actions Under the Clean Water Act . ...............................186

EPA Actions Under the Safe Drinking Water Act . ........................187

EPA Actions Under the Federal Insecticide, Fungicide, and Rodenticide Act ..188

EPA Actions Under the Toxic Substances Control Act..... . ...............189

EPA Actions Under the Resource Conservation and Recovery Act . .........190

EPA Actions Under the Comprehensive Environmental Response,

Compensation, and Liability Act. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191

Assessments by EPA’s Carcinogen Assessment Group . . . . . . . . . . . . ..........191

No Apparent Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................192

Agency Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....................192

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................192

Figure

Figure No. Page

5-1. Agency Actions on Annual Report and Positive NCI/NTP Chemicals .. ...194

Tables

Table No. Page

5-1. Summary of NCI/NTP Test Results . . . . . . . . . . . ........................175

5-2. Agency Actions on Positive NCI/NTP Chemicals . ......................179

5-3. Agency Actions on Positive NCI/NTP Chemical and Annual Report

Chemicals—Actions and Jurisdiction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .193
Chapter 5

Agency Responses to the Annual Report

on Carcinogens and NCI/NTP Test Results

INTRODUCTION

In this chapter, OTA examines Federal agency

responses to the list of carcinogens in the Annual

Report on Carcinogens and to positive results for

chemicals tested in the carcinogenicity bioassays

conducted by the National Cancer Institute (NCI)

and National Toxicology Program (NTP). This

analysis only provides summary information

about the chemicals that may be considered carcinogenic based on the Annual Report or positive NCI/NTP bioassay results and describes the

extent of agency actions on these chemicals. (As

in the rest of this background paper the term

“chemical” is used here broadly to include substances, mixtures, groups of substances, and exposures. )

Not all factors important in regulatory decisions

are encompassed by the present analysis. In particular, estimates of the risk presented by these

chemicals (including the qualitative weight of the

evidence, quantitative potency estimates, and

quantitative exposure estimates), agency judgments that these risks are reasonable or unreasonable, the availability of control technologies, and

the costs of controls are not considered here. As

discussed in chapter 3, another important issue

is the time needed to develop, propose, issue, defend, and implement new regulations. This analysis, however, does not discuss the time agencies

take to respond to identified carcinogenic chemicals. Finally, OTA did not attempt to evaluate

the level of protection provided by the regulations

that have been issued. The analysis focused just

on whether or not regulations had been issued.

THE ANNUAL REPORT ON CARCINOGENS

History of the Annual Report

The Annual Report on Carcinogens was mandated by Congress in the 1978 amendments to the

Community Mental Health Centers Act (Public

Law 95-622). The idea of an annual report was

first raised publicly in oversight hearings on the

NCI held in March of that year. Witnesses testified that no agency kept a comprehensive list of

carcinogenic chemicals, and that while some

chemicals were regulated by one agency, the same

chemicals were not regulated by other agencies.

Representative Andrew Maguire introduced a bill

to require that NCI publish a list of carcinogenic

chemicals. He hoped that the report would educate the public, serve as a point of reference for

scientists and regulators, and evaluate the activities of the regulatory agencies, who are not immune to pressure from the outside (113).

The bill first passed by the House of Representatives had specified that NCI would be responsible for the report and that the report should contain

●

●

●

three elements:

a list of all known or suspected carcinogens,

information concerning the nature of exposure and number of individuals exposed,

and

an evaluation of the efficacy of existing reg- - -

ulatory standards designed to control suspected carcinogens (197).

In the final version, responsibility was given to

the Department of Health and Human Services

(DHHS), and “suspected carcinogens” was

changed to “substances . . . reasonably anticipated to be carcinogens.” As enacted, the law requires that the report include the following:

. . . a list of all substances (i) which either are

known to be carcinogens or may reasonably be

anticipated to be carcinogens and (ii) to which

a significant number of persons residing in the

United States are exposed (Public Law 95-622).

171
172

The provision mandating the evaluation of existing standards was modified to require that the Annual Report determine the following information:

(i) each substance . . . for which no effluent,

ambient or exposure standard has been established by a Federal agency, and

(ii) for each [existing] standard . . . the extent

to which, on the basis of available medical, scientific, or other data, such standard and the implementation of such standard by the agency decrease the risk to public health from exposure to

the substance (Public Law 95-622).

Finally, the law requires that the Annual Report

describe requests from Federal agencies for carcinogenicity testing and the responses of DHHS

to those requests.

The original sponsor of this legislation, Andrew

Maguire, and Paul Rogers, the chair of the subcommittee from which the legislation was originally reported, both argue that these changes did

not alter the intent of the original legislation

(113,177). Paul Rogers described the regulatory

importance of the Annual Report:

The intention of the legislation was that listing in the annual report would be a first step in

regulation, one triggering a review by the agencies responsible for enforcing various laws regulating carcinogens (175).

Development of the Annual Report

In the Annual Report, “known carcinogens” are

defined to be human carcinogens, while animal

carcinogens are deemed to be “substances . . . reasonably anticipated to be carcinogens. ” New

chemicals are usually included in the Annual Report after testing positive in NCI/NTP bioassays

in both sexes of one species and in at least one

sex of a second species.1

The substances to be included in the Annual

Report are selected by an interagency committee,

with representatives from NCI, U.S. Consumer

Product Safety Commission (CPSC), Environmental Protection Agency (EPA), Food and Drug

Administration (FDA), National Institute of Environmental Health Sciences (NIEHS), National

Institute for Occupational Safety and Health

(NIOSH), National Library of Medicine (NLM),

and Occupational Safety and Health Administration (OSHA). The committee compiles a list of

chemicals based on the previous Annual Report,

International Agency for Research on Cancer

(IARC) reports, NTP animal testing results,2 other

peer-reviewed carcinogenesis studies, and data on

chemical exposures from a variety of sources. The

draft list is published for public comment, after

which the committee makes its final selections.

While the legislation provided for a yearly report, in practice the reports have not been issued

annually. Mandated by Congress in November

1978, the first report was dated July 1980; the second, December 1981; and the third, September

1983. The fourth report is dated “1985,” although

copies were not widely available until mid-1986.

Much of the delay in issuing 1985 report was due

to review within DHHS (26).

This year, for the first time, NTP held a public

meeting to receive comments on chemicals to be

listed in the fifth Annual Report. A number of

interested trade associations, unions, public interest organizations, and individuals presented

comments on the Annual Report. Many of the individuals and groups thought highly of the Annual Report and found it to be a useful reference.

Some participants suggested that more chemicals

be listed by using less stringent selection criteria.

In addition, they wanted the Annual Report to

focus attention on chemicals that should be subject to further regulatory activity (113,173,363).

A number of trade associations expressed concern, however, about the process used to develop

the Annual Report. These groups suggested that

NTP adopt written guidelines for determining listing in the Annual Report (specifying, in particular, the use of a “weight of the evidence” approach), that NTP develop more information on

exposures (especially evaluating likely human exposures in relation to animal test exposures), and,

in developing the report, that NTP give earlier

public notice, more explanation of the rationale

IUsing the terms of the next section, this means three or four positive experiments (clear evidence or some evidence) in an NTP

bioassay.

‘That these results are included leads to some overlap in this chapter between discussions of agency responses to Annual Report listings and positive results of NCI/NTP tests.
173

for chemical selection, and greater opportunity

for public participation. Some participants also

expressed concern that NTP was using the conclusions of an international organization, the

IARC, to determine listing in the Annual Report

(4,30,80).

Increased interest in the Annual Report has

arisen in part because it is now being used to trigger regulatory requirements. OSHA is using the

Annual Report as part of its hazard communication or “labeling” standard. That standard requires, first, that chemical manufacturers assess

the hazards of the chemicals they produce and

transmit this information to employers and employees and second, that employers provide hazard information to employees through a system

of warning labels, employee training about hazardous chemicals, and employee access to material safety data sheets. The OSHA standard mandates that a chemical be considered a carcinogen

(and hazardous) if it is included in the Annual Report or the IARC monograph series, or if it is regulated by OSHA as a carcinogen. The material

safety data sheet for the chemical must also indicate this.

Several State worker and community “right to

know” laws also use the Annual Report to trigger coverage. In addition, the recently enacted

California proposition 65 (“the 1986 Safe Drinking Water and Toxic Enforcement Act”) establishes rules and warning requirements for chemicals “known to cause cancer. ” To identify these

substances, proposition 65 refers to the OSHA

hazard communication standard, which in turn

refers to the Annual Report.

Contents of the Annual Report

The Annual Report covers the reasons for listing substances; summaries of chemical properties;

descriptions of production, uses, and exposures;

and information on reported regulatory actions.

Much of this information is provided by the participating agencies themselves. To a very limited

extent, the Annual Report describes some of the

exposure reductions associated with agency regulations.

The Annual Report has not attempted to identify regulatory “gaps”—areas where regulations

appear to be needed—or to evaluate whether current standards are sufficiently protective. Instead,

the Annual Report presents only descriptive information on the regulatory standards that have

been issued.

Listed Chemicals

The first Annual Report listed only the 26 chemicals that IARC had determined to be human carcinogens. The second Annual Report listed 25

chemicals known to be carcinogenic based on human data3 and 63 chemicals reasonably anticipated to be carcinogenic. The third Annual Report listed 22 chemicals known to be carcinogenic

and 95 chemicals reasonably anticipated to be carcinogenic. In the fourth Annual Report, 29 chemicals are listed as human carcinogens and 119 as

reasonably anticipated to be carcinogenic.

The fourth Annual Report lists 148 chemicals,

chemical groups, mixtures, and exposures altogether. NTP has grouped these chemicals into

12 categories:

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

natural substances;

food or cosmetic additives;

pesticides;

drugs;

dyes, dye intermediates and pigments;

combustion products;

solvents;

metals and metal compounds occurring in

mining, extraction, and refining processes;

analytical and research chemicals;

miscellaneous use chemicals;

various industrial chemicals and byproducts; and

occupational exposures with unknown etiologic agents. -

For this analysis, OTA has adjusted the total to

eliminate double counting, yielding a total of 145.4

3

IARC had r&valuated and reclassified Chloramphenicol, and for

this reason, changes between the second and third reports, as well

as between the third and fourth involve reevaluation of other chemicals by the committee compiling the Annual Report.

4

Specifica11y, this adjustment affects “nickel” and “nickel refining, ” “Phenacetin” and “analgesic mixtures containing Phenacetin, ”

and “certain combined chemotherapy” with some chemotherapeutic agents. In the discussion below, the number of actions does not

always add correctly to the total indicated, usually because some

chemical has been addressed in several different ways.
174

Some well-known carcinogens have not been

included in the Annual Report lists, although the

introduction briefly mentions several of them:

tobacco smoke, alcohol, ionizing radiation, viruses, and ultraviolet radiation (including sunlight). Additionally, though underground hematite mining is listed, underground uranium mining,

which exposes workers to radon daughters, is not.

NTP uses the IARC lists of human and animal

carcinogens as a source, but several agents and

processes on the IARC list have not been listed

NCI/NTP CHEMICAL TEST RESULTS

Classification of Test Results

Through June 1, 1987, 308 different substances

and mixtures have been tested in long-term animal bioassays sponsored by NCI and NTP. The

number of studies totals 327; 17 chemicals have

been studied twice and one (trichloroethylene) has

been studied three times (85).

Published reviews of these studies summarize

the results for the nearly 200 substances tested

when the program was under NCI (30,32,73) and

the just over 100 conducted since then under NTP

(84,85,91,92).

In this analysis, NCI/NTP test results are

grouped by the level of evidence for carcinogenicity that they provide and then Federal agency

responses to these results through risk assessments

and regulations are examined. The “level of evidence” is determined for each particular species

and sex. Separate results are given for each “expediment, ” that is, each combination of species

and sex in a study: male rats, female rats, male

mice, and female mice. Results of NCI-conducted

bioassays and the early bioassays conducted by

NTP were described in the technical reports as

“positive, “ “negative, “ “equivocal, ” and “inadequate.” Since June 1983, NTP has used five categories for levels of evidence, using either “clear

evidence” or “some evidence” for positive results.

Thus, in the current NTP scheme, the results of

each experiment are classified as clear evidence,

some evidence, equivocal evidence, inadequate

evidence, or no evidence of carcinogenicity (see

ch. 2).

by NTP. With regard to the IARC listing of exposures under Boot and Shoe Manufacture and

Repair and Furniture Manufacture, the report

states that, while NTP “does not disagree with

these judgments, “ it does not list these processes

because the particular causes or process steps associated with cancer in these cases have not been

isolated. NTP also notes that these processes vary

significantly among countries and have also

changed, thus changing the nature of the exposures.

NTP test results are examined by peer review,

with the reviewing committee classifying the results. Results are then published as technical

reports and in summary form. NTP has not developed any general classification or ranking that

considers the results of all experiments (for all

sexes and species) together.

OTA Grouping of Test Results

OTA has used the most recent summary of results to classify the chemicals tested in NCI/NTP

bioassays (85).5 In that summary, each study was

classified by the scheme in use at the time of the

study, relying on the conclusions published in the

study’s technical report. While the summary covers all test results up to June 1987, OTA has included only those chemicals for which the technical report had been printed, or which had

already been subject to peer review and data audit, as of the September 1986 NTP Management

Status Report.

Table 5-1 summarizes the number of substances

in each evidence category. In total, 284 chemicals were tested in 298 separate studies. b In this

analysis, 13 chemicals have been tested twice and

1 three times. In most cases, each study represents

four “experiments”: male rats, female rats, male

mice, and female mice. In some cases, hamsters

were the second species tested; in a few cases, only

5

0TA will refer to the chemicals tested by NCI/NTP that tested

positive in at least one experiment as “positive NC1/NTP chemicals. ”

‘The number of studies here is fewer than that given above (306)

because OTA’S cutoff date was September 1986, while for the review above the date used was June 1, 1987 (85).
175

Table 5-l.— Summary of NCI/NTP Test Results

Number of chemicals

(Grouping duplicate

Number of tests in highest level

Level of evidence tests of evidence)

4 positive . . . . . . . . . . . . 38 36

3 positive . . . . . . . . . . . . 25 25

2 positive . . . . . . . . . . . . 55 51

1 positive . . . . . . . . . . . . 33 32

Total positive ., . . . . 151 144

Equivocal evidence . . . 36 35

Inadequate test . . . . . . . 11 9

All negative . . . . . . . . . . 100 96

Total . . . . . . . . . . . . . . 298 284

SOURCE Off Ice of Technology Assessment, 1987.

male and female animals of one species were

tested.

For this analysis, OTA has grouped chemicals

by the number of species and sex combinations

that show a particular level of evidence. The first

group consists of substances for which all four experiments showed positive results (“positive” for

older tests, “clear evidence of carcinogenicity” or

“some evidence of carcinogenicity” for later tests).

The second group consists of chemicals testing

positive in three of four experiments, that is, positive in both sexes of one species, but only one sex

of the second species. The third group includes

chemicals yielding two positive experiments: either positive results in both sexes of one species

and equivocal evidence, inadequate evidence, or

negative evidence in the second species, or positive

results in a mixed fashion in two experiments (e.g.,

positive in male rats and female mice).’ The fourth

7

Because there is a high concordance of positive results within

a species, a two-positive result in two species may be stronger evidence for carcinogenicity than a two-positive result in one species.

For the chemicals analyzed by OTA, 8 of the 51 two-positive results are positive in two species. However, OTA has not analyzed

these two kinds of two-positive results separately.

group covers chemicals with one positive experiment. Remaining test results are classified equivocal, inadequate, or negative (“no evidence”),

When a chemical has been tested more than

once, values on the table represent the highest

level of evidence for the chemical. For example,

test results for tetrachloroethylene (perchloroethylene) were published in 1977 and 1986. The 1977

results were inadequate in male and female rats

and positive in male and female mice. The 1986

results consisted of clear evidence in male rats,

some evidence in female rats, and clear evidence

in male and female mice. The first test results are

considered two positives; the second test results

as four. Thus, tetrachloroethylene was grouped

with the other chemicals yielding four positive results. When counting the number of chemicals for

the second column of table 5-1, multiple tests of

the same chemical were counted only once.

As shown in table 5-1, using this method of

grouping, 36 chemicals (as opposed to studies)

yielded four positive results, 25 three positives,

51 two positives, and 32 one positive. Chemicals

that failed to yield at least one positive experiment were not included in analyzing agency responses to test results. The total number of chemicals analyzed by OTA was thus 144. Of the 144,

61 chemicals tested positive in three or four experiments.

Some factors have not been incorporated in the

present analysis: affected tumor sites in the animals, whether both high and low doses (or all

three doses in a three-dose experiment) produced

a response, or the estimated potency of chemicals. Also, the grouping of chemicals here is based

solely on results of NCI/NTP tests. OTA has not

used results from other animal bioassays or from

epidemiologic studies.

OTA ANALYSIS OF ACTIONS, EXPOSURES,

AND AGENCY JURISDICTIONS

Agencies and Programs Analyzed cals tested in NCI/NTP bioassays (EPA, FDA,

OSHA, and CPSC), and two organizations with

risk assessment responsibilities (NIOSH and EPA’s

In this analysis, OTA covers the major agen- Carcinogen Assessment Group (CAG)). EPA was

cies and programs authorized to regulate chemi- analyzed by the following major program areas:
176

●

●

●

●

●

●

●

●

hazardous air pollutants listed under section

112 of the Clean Air Act (CAA);

chemicals covered by water quality criteria

documents issued under the Clean Water Act

(CWA);

chemicals covered by interim drinking water

standards issued and recommended and maximum contaminant levels (RMCLS and

MCLS) proposed under the Safe Drinking

Water Act (SDWA);

pesticides canceled, regulated, or voluntarily removed from the market under the Federal Insecticide, Fungicide, and Rodenticide

Act (FIFRA);

chemicals evaluated, designated, or regulated

under sections 4 and 6 of the Toxic Substances Control Act (TSCA);8

chemicals listed as hazardous wastes and as

hazardous constituents of wastes (Appendix

VIII) by the Office of Solid Waste under the

Resource Conservation and Recovery Act

(RCRA);

chemicals for which reportable quantities

were established under the Comprehensive

Environmental Response, Compensation,

and Liability Act (CERCLA); and

chemicals assessed by the Carcinogen Assessment Group (CAG).

Determining Agency Actions on

Annual Report Chemicals

The source for the discussion below on carcinogen regulation is the Annual Report itself. 9 Regulations on carcinogens that are based on noncarcinogenic effects are also covered in the

discussion.

Determining Agency Actions on

NCI/NTP-Tested Chemicals

To determine which tested chemicals have been

subject to regulatory action, OTA sent a list of

all chemicals tested in NCI/NTP bioassays to

8

TSCA Interagency Testing Committee recommendations and

EPA-issued test rules have been excluded.

‘Throughout this discussion, references to the Annual Report are

to the fourth report. OTA will refer to the chemicals as “Annual

Report chemicals. ”

EPA, FDA, OSHA, and CPSC. OTA asked that

they indicate which substances they had evaluated for carcinogenicity, which they had prepared

a risk assessment for, which they had proposed

to regulate, and which they had issued final regulations on. Federal agency responses were supplemented with information OTA gathered from

other sources (see ch. 3).

Exposure Information

The present analysis faced one particularly difficult and important problem—determining exposures. Not every chemical tested by NCI/NTP

is actually in commerce, and some have never

been in commerce. Some are trace contaminants,

chemical byproducts, or intermediates in closed

industrial chemical processes, to which exposures

may be limited. Others are found in consumer

products and foods at relatively low concentrations, but because millions of people are exposed,

the potential for harm may be great. Other substances analyzed here may be found in ambient

air, surface water, or drinking water supplies.

Which agencies and programs (or statutes)

should be concerned about a chemical depends

on the nature and extent of exposure. Unfortunately, comprehensive data on toxic chemical exposures do not exist. For example, data on particular environmental media (e.g., drinking water)

derive from studies measuring the concentrations

of particular chemicals (e.g., EPA’s 126 priority

water pollutants), studies which of course do not

determine the presence of all chemicals of interest.

Lacking information on exposures, agencies frequently use chemical production data to set priorities. To obtain such production data, OTA

searched the Hazardous Substance Data Bank

(HSDB) of TOXNET, a database maintained by

NLM, which includes information on production

levels estimated by the Stanford Research Institute (SRI).

While the SRI data on chemical production are

frequently used, they also have limitations. First,

SRI has not made production volume estimates

for every chemical of interest in this analysis. Second, HSDB does not provide any information at

all on some chemicals included in this analysis.

(Even if SRI had prepared estimates in these cases,
177

OTA was not able to use those estimates because

the information was not contained in HSDB. )

Third, production level is an imperfect proxy for

what is really at interest—the actual levels of exposure. For example, a chemical can be produced

and consumed in a closed system with relatively

little exposure to workers or the environment.

Production volume statistics by themselves do not

reflect such situations. Nonetheless, production

volume is frequently the only information available and is often used when describing and ranking the potential risks of different chemicals.

OTA also obtained information from the NIOSHconducted National Occupational Hazard Survey

(1972-74) and its update, the National Occupational Exposure Survey (1981-83). These surveys

present the results of walk-through observations

of chemicals found in workplaces representing the

manufacturing and public utility sectors.

OTA also asked each agency to indicate which

chemicals might be present in those media or exposure situations of interest to the agency. OTA

used information on production volumes, potential worker exposures, uses of chemicals, and

agency responses to narrow the list of chemicals

for each agency or program to the chemicals of

potential regulatory interest. This information

was used to define a regulatory jurisdiction for

each agency or program. In addition, OTA automatically included in an agency’s jurisdiction

those chemicals that the agency has already acted

o n .

Regulatory Jurisdictions

In all cases, a chemical is included in the OTAdefined jurisdiction for an agency or program if

the agency or program has already acted on that

chemical. OTA supplemented this with other information to define the agency jurisdictions for

chemicals they have not acted on.

FDA actions were analyzed in the following categories: 1) chemicals evaluated, regulated, or

banned in foods, color additives, and cosmetics;

10A banned chemical will no longer be in production and thus

would not be within a regulatory jurisdiction defined exclusively

by production data. In such a case, the chemical would still be included in the regulatory jurisdiction by OTA analysis,

2) animal drugs; and 3) human drugs. Regulatory

jurisdiction was based on information on chemical uses and responses from FDA staff concerning chemicals FDA had evaluated.

OSHA’s and NIOSH’s jurisdictions were defined based on whether a chemical was detected

in the NIOSH occupational hazard and exposure

surveys or is produced in quantities greater than

1 million pounds annually. OTA did not make

distinctions based on the number of employees

potentially exposed because that information is

either fairly old (deriving from the 1972-74 survey) or still incomplete (data from the 1981-83 survey do not yet cover exposures to trade name

products).

To determine a regulatory jurisdiction for

CPSC, OTA obtained its staff’s indications on the

identities and levels of chemicals present in consumer products and on which chemicals present

actual or possible consumer exposures.

For hazardous air pollutants, EPA has compiled

a database on chemicals of interest and specified

methods and developed a computer program for

ranking pollutants. This system is called the Modified Hazardous Air Pollutant Prioritization System (MHAPPS) (167). OTA did not use the EPA

priority-setting computer program. Rather, OTA

searched the MHAPPS database of 609 chemicals

for the positive NCI/NTP and Annual Report

chemicals and for chemicals that were produced

in quantities exceeding 1 million pounds per year

with either of the following characteristics:

● a vapor pressure > 100 mm Hg or a boiling

point < 80° C, or

● a vapor pressure > 24 mm Hg and <100

mm Hg or a boiling point > 800 C and <

100° c.

These characteristics are those specified by

MHAPPS methods (167). The vapor pressure and

boiling point criteria were used to narrow attention to the most volatile chemicals. While dusts,

such as those of arsenic or chromium, may also

present problems as hazardous air pollutants, they

were not included in this analysis,

To define the jurisdiction for EPA administration of the Clean Water Act, OTA used information from an EPA database—the Historical Fre-
178

quency Database—prepared for EPA’s Effluent

Guidelines Division, with water samples collected

from 1976 to 1979 and computer data entry from

1977 to 1981. That a chemical is in the database

indicates it was detected in effluent streams associated with discharges into surface water. That

a chemical is not included in the database does

not necessarily indicate that it is not a potential

water pollutant, only that it was not detected

using a particular set of methods and water samples. The chemical’s being present in the database,

on the other hand, indicates that it is a potential

pollutant in at least some locations (113).

To analyze actions on drinking water, OTA requested information from the staff of EPA’s Office on Drinking Water on positive NCI/NTP

chemicals and Annual Report chemicals known

to be present or that might be present in drinking water. In addition, EPA staff indicated which

chemicals on these two lists had been detected in

drinking water, but at levels that they judged “not

significant” (36).

For information on pesticides, OTA asked staff

of the EPA pesticide program to indicate which

chemicals on the two lists were used as active ingredients and inert ingredients in pesticides (21).

TSCA’s jurisdiction is all toxic chemicals. Under

TSCA, regulatory treatment differs if a chemical

RESULTS OF OTA ANALYSIS

FDA Actions on Foods and Cosmetics

Annual Report Chemicals

Two Annual Report chemicals are in its category “food or cosmetic additives.” But a number

of chemicals in other Annual Report categories

contaminate food or cosmetic additives or are

considered indirect additives. These chemicals

have also been acted on or evaluated by FDA.

As described in chapter 3, the major types of materials FDA evaluates for potential hazards in

foods and cosmetics are direct food additives, indirect food additives, color additives, other ingredients in cosmetics, and unavoidable environmental contaminants in food.

is in commerce or is not in commerce. Therefore,

distinctions were made between chemicals that are

produced in large quantity (more than 1 million

pounds annually), produced in smaller quantity

(less than 1 million pounds), not produced, or

have unknown status because there were no entries on them in HSDB.

The regulatory jurisdictions for RCRA and

CERCLA for this analysis are Annual Report and

positive NCI/NTP chemicals.

Table 5-2 summarizes, by level of evidence,

the number of positive NCI/NTP chemicals that

have been acted on by the various agencies and

programs.

Review of OTA Analysis

A first draft of this analysis was sent to the

agencies in February 1987 in preparation for an

OTA workshop in March 1987, to which agency

staff and representatives of other groups were invited. Again, agencies were asked to indicate

which of the Annual Report and NCI/NTP chemicals they had acted on and to provide information on regulatory jurisdictions. A second draft

was sent to the agencies in May 1987, again requesting comments and providing an opportunity

for errors to be corrected.

A few Annual Report chemicals are or were direct food additives: safrole and cadmium have

been banned as additives to food (though the action taken on cadmium was not based on its carcinogenicity). FDA proposed to ban saccharin,

but Congress acted to prevent the ban. Two more

Annual Report chemicals, nitrilotriacetic acid and

hydrazine, are added to boiler water and are considered secondary direct additives. FDA has not

banned their use, but instead has set regulations

specifying the safe use of these substances.

Fifteen Annual Report carcinogens are indirect

food additives or were considered potential indirect additives. Indirect additives are usually substances that may migrate into food from packag-
179

Table 5.2.—Agency Actions on Positive NCI/NTP Chemicals

Level of evidence

Four Three Two One All positive

positives positives positives positive NCI/NTP chemicals

Number of chemicals . . . . . . . . . . . . . . . . . . . . . . . .

No activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CAG assessment . . . . . . . . . . . . . . . . . . . . . . . . . . .

RCRA listed or App. Vlll ... , . . . . . . . . . . . . . . . . .

CERCLA

Listed , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Proposed RQ adjust. . . . . . . . . . . . . . . . . . . . . . .

CWA WQC or standards . . . . . . . . . . . . . . . . . . . . .

SDWA

Interim std. (1975 and 1979) . . . . . . . . . . . . . . . .

Proposed and final RMCL . . . . . . . . . . . . . . . . . .

CAA listed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

TSCA

Rule 8a or 8d or CHIP . . . . . . . . . . . . . . . . . . . . .

4(f) review/SNUR/Sec. 6 . . . . . . . . . . . . . . . . . . . .

FIFRA

Susp. Cane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Vol. Cane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Food and Cosmetics (Ban, SUR, or

action level) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

FDA

Animal drugs (revoked/withdrawn) . . . . . . . . . . .

Human drugs (labeled/withdrawn) . . . . . . . . . . .

NIOSH recommendation . . . . . . . . . . . . . . . . . . . . .

OSHA

Noncancer std. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cancer std. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CPSC

Ban/restricted . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Voluntary reduction only . . . . . . . . . . . . . . . . . . .

36

13

25

10

3

8

51

12

11

17

32

8

2

2

144

43

6 22

14 41

14

11

6

8

4

1

19

15

5

6

2

2

47

32

14

1

—

1

5

—

2

11

2

—

5

1

—

1

— 1

14

2

8

—

20

2

11

1

53

5

2

2

6

—

1

1

9

4

—

1

4 3 7 3 17

2

—

15

1

2

2

1

1

3

4

6

31

—

3

11

11

1

4

—

10

—

2

1

27

2

2

2

1

—

3

5

—

—

—

, 3

SOURCE Office of Technology Assessment, 1987

ing material. FDA prohibited the use of materials

that contain three of these substances (4,4’-methylenebis (2-chloroaniline), ethylene thiourea, and

2,4-diaminotoluene). FDA proposed to ban the

use of three other chemicals (hydrazine, 2-nitropropane, and chloroform [in food contact articles]), but final action was never taken.

to prohibit use of these bottles.11 In the 1980s,

FDA took action to permit their use. It is currently

evaluating the risks presented by another two potential indirect additives (di(2-ethylhexyl)phthalate (DEHP)and4,4’-methylenedianiline [MDA]).

Fifteen other Annual Report chemicals contaminate direct food or color additives. Urethane is

a contaminant of diethylpyrocarbonate (DEPC),

which was banned. Benzidine, 4-aminobiphenyl,

2-naphthylamine, o-toluidine, and polycyclic aromatic hydrocarbons contaminate various color

For five Annual Report chemicals considered

potential indirect additives, FDA chose not to ban

the packaging materials, but issued rules for safe

use of the material (1,2 -dichloroethane, dimethyl

sulfate, Epichlorohydrin, toluene diisocyanate,

chromium [though the last was not for carcinogenicity]). Two Annual Report carcinogens ,

acrylonitrile and vinyl chloride, may migrate from

certain plastic bottles. In the 1970s, FDA proposed

I IA[though at the time, FDA was not regulating aCryl Onitrile as

a suspect carcinogen. Their action to prohibit this particular bottle

was overturned in court.
180

additives. 12 As described in chapter 3, FDA has

changed the approach it takes when a color additive is contaminated with carcinogenic impurities. Prior to 1982, FDA banned several such additives. After 1982, following its new policy on

impurities, FDA has permitted these color additives.

In evaluating other cosmetic ingredients, FDA

has banned the addition of chloroform to cosmetics and allows the use of lead acetate, 2,4-

diaminoanisole sulfate, and 4-chloro-o-phenylenediamine in hair dyes. It has set a limit, however, on the amount of lead acetate permitted in

these dyes. For the other two chemicals, FDA had

attempted to require a product warning label on

coal tar dyes. This requirement was stayed by

court order. FDA has not taken action to reinstate the warning label.

Finally, with regard to environmental contaminants, FDA has set food tolerances for polychlorinated biphenyls (PCBs) and action levels for 15

Annual Report chemicals, including aflatoxins,

several pesticides (DDT, ethylene dibromide,

Kepone, Mirex, Toxaphene), polybrominated biphenyls, and cadmium (though this FDA action

was not based on carcinogenicity). FDA is also

currently considering a petition to reduce permissible levels of urethane (a product of the fermentation process) found in wine and other alcoholic

beverages.

Considering all FDA activities together and

eliminating double counting of chemicals yields

a total of 52 different Annual Report carcinogens

examined by FDA. Of these, 9 individual chemicals and one group of 10 chemicals, polycyclic

aromatic hydrocarbons (PAHs), are associated

with materials banned by FDA. Twelve chemicals are associated with materials FDA has issued

safe use rules on or has permanently listed (as permissible color additives), and three Annual Report chemicals are permissible ingredients in hair

dyes. For 16 chemicals, tolerances or action levels

have been set. Some carcinogens in the Annual

Report are subjects of proposed bans that were

1

2

0TA has not determined which of the 10 polycyclic aromatic

hydrocarbons listed in the Annual Report actually contaminated

carbon black and graphite, the colors in question. For simplicity,

all are included in this discussion.

never finalized. FDA is still evaluating at least

three (DEHP, MDA, and urethane in alcoholic

beverages).

Of the 52 chemicals, 46 have been subject to

final FDA actions consisting of bans, safe use

rules, permanent listing decisions, or the setting

of tolerances or action levels. Ten chemicals have

not been subject to final actions, although sometimes this lack of action concerns only some

uses. 13

Excluding environmental contaminants, 37

chemicals are associated with food or color additives, and potentially subject to bans under provisions of the Food, Drug, and Cosmetic Act. Of

these, 19 (including 10 PAHs) are associated with

materials actually banned by FDA. For most of

the remaining chemicals, FDA has specified safe

use rules.

Positive NCI/NTP Chemicals

Most of the bioassay information evaluated by

FDA for food and cosmetic ingredients is obtained

from testing FDA requires from the ingredients’

sponsors. In a few cases, direct food or color additives or potential indirect additives have been

tested by NCI/NTP. More frequently, the NCI/

NTP bioassay program has tested chemicals that

may be present as impurities in additives or cosmetics.

FDA actions on positive NCI/NTP chemicals

may be broken down based on the use of the material. One direct food additive has been banned

(cinnamyl anthranilate). Currently pending is a

proposed safe use rule to allow use of methylene

chloride to decaffeinate coffee. FDA has also proposed to ban use of trichloroethylene for coffee

decaffeination and cosmetic uses. Although that

proposal was never issued in final form, those uses

of trichloroethylene have apparently stopped.

One color additive, D&C Red No.9, is in the

group of 144 positive test result chemicals, having tested positive in male rats. As described in

chapter 3, FDA has permanently listed this color

additive.

13 Hence these chemicals total 52 because several chemicals are in

both groups.
181

FDA has taken some action on three positive

NCI/NTP chemicals that are potential indirect additives. It has proposed to ban chloroform from

food contact materials. Safe use rules have been

issued for 1,4-dioxane and 1,1, 2-trichloroethane.

Safe use rules have also been issued for three

contaminants of color additives: aniline hydrochloride, azobenzene, and CI Vat Yellow No.4.

Ten other positive NCI/NTP chemicals have

or had cosmetic uses. One has been banned from

cosmetics (chloroform); FDA has proposed banning one other from cosmetics (methylene chloride). Seven positive NCI/NTP chemicals are used

in hair dyes (2,4 -diaminoanisole sulfate, 4-chlorom-phenylenediam ine, 4-chloro-o-phenylenediamine, 2-nitro-p-pheny ~enediamine, 4-amino-2-

nitrophenol, HC Blue No.1, and 2,4-diaminotoluene). These dyes are all currently permitted. As

mentioned above, FDA acted to require a warning label for coal tar hair dyes, but that requirement was overturned by court order. In addition,

selenium sulfide is allowed for use in dandruff

shampoo.

Action levels or food tolerances have been issued for eight positive NCI/NTP chemicals.

Considering these FDA actions together and

eliminating double counting yields a total of 17

positive NCI/NTP chemicals on which FDA has

taken some final action; for 2 other chemicals it

has proposed action. A greater number of positive NCI/NTP chemicals, 31, have only been

evaluated by FDA. These include 9 chemicals with

four positive results, 3 with three positives, 10

with two positives, and 9 with one positive result. The evaluations include exposure assessments

and risk assessments, which were conducted because FDA thought that the chemicals might be

found in food additives or cosmetics.

The scope of FDA jurisdiction is thus 48 positive NCI/NTP chemicals. Of these, 19 had three

or four positive experiments. FDA has issued final bans, safe use rules, or action levels or tolerances for seven of these.

FDA Actions on Human Drugs

Annual Report Chemicals

Thirty-four Annual Report chemicals have or

had uses as human drugs. Thirty-one of these are

listed in the Annual Report as “drugs.” Several

of these listings, however, may represent double

counting: “phenacetin” and “analgesic mixtures

containing phenacetin” are listed separately, and

“certain combined chemotherapy for lymphomas”

overlaps with the listing of specific drugs included

in those therapies. For this discussion, therefore,

OTA will count 29 chemicals as “drugs.” In addition, five chemicals have or had drug uses, or

might be found in drug products, but are listed

in different categories: thorium dioxide (listed under “miscellaneous uses”), chloroform (listed under “solvents”), coal tar (listed under “occupational exposure with unknown etiologic agent”),

urethane and vinyl chloride (both listed under “industrial chemicals and byproducts”).

Of the 29 chemicals listed as “drugs,” 25 are

on the market with physicians’ labeling information warning of carcinogenic effects, 2 have been

removed from the market or were never approved

(Phenacetin) and (Chlornaphazine), and 2 are approved drugs on the market (selenium sulfide and

Propylthiouracil). Selenium sulfide is approved

for use in dandruff shampoos and for topical treatment of fungal infections. The labeling in this case

only indicates the negative results of skin-painting

experiments in mice. There is no labeling information on propylthiouracil in the Physician

Desk Reference.

The remaining five chemicals in nondrug categories are the following:

1.

2.

3.

Thorium dioxide, which FDA approved for

x-ray imaging, although labeling restricts use

to patients with limited life expectancy.

Chloroform, for which FDA banned drug

uses in 1976.

Coal tar, which has medical use as a topical

antifungal agent and in the treatment of psoriasis. It was declared to be unsafe for overthe-counter use by an FDA advisory panel

in 1982. The final monograph on this decision is still being prepared for publication.
182

4.

5.

Urethane, which was removed from the market in 1970 because it was determined to be

ineffective as a drug.

Vinyl chloride, for which FDA announced

that- a new drug application would be required for drug use to be permissible.

Thus there are 34 Annual Report chemicals with

drug uses: 5 were removed from the market or

never approved, 26 are approved for use but with

the physicians’ labeling information warning of

potential carcinogenic effects, 2 were approved

for topical use, and 1 was approved for use without any labeling information available.

Positive NCI/NTP Chemicals

Twelve positive NCI/NTP chemicals were indicated to be used in drugs, many as anticancer

agents. All drugs are permitted to be on the market by virtue of some FDA regulatory action (e.g.,

through approval of a new drug application in

the case of new drugs). But for this analysis, the

actions of interest are regulatory and directed

toward the carcinogenic risk that may be presented by these drugs. Thus only actions to remove a drug from the market, restrict its uses,

or require warning labels are considered as regulatory actions. By this standard, two positive

NCI/NTP chemicals have been regulated: chloroform was banned from drugs, and FDA required

physician labeling for Reserpine (three positives)

to warn of animal carcinogenicity. Physician

labeling fors of the 11 remaining drugs warns of

potential carcinogenicity. The final 6 drugs are

not included in the latest edition of the Physician’s

Desk Reference and may never have gotten past

the investigational stage. All were intended for

use as anticancer drugs. Finally, although it is not

a drug, DEHP, which is used to make blood bags,

may migrate from those bags into the blood stored

inside.

FDA Actions on Animal Drugs

Annual Report Chemicals

Six Annual Report chemicals are used as drugs

for food-producing animals. FDA revoked approval for one of these—diethylstilbestrol (DES)–

while for a second, Reserpine, the sponsor withdrew the application for approval. The remaining four substances and classes of substances—

conjugated estrogens, nonconjugated estrogens,

progesterone, and iron dextran complex—may be

used in animals.

Positive NCI/NTP Chemicals

Five positive NCI/NTP chemicals have uses as

animal drugs or are related to animal drugs. FDA

has revoked approval for four of these. The fifth

chemical, Zearalenone, is related to the animal

drug Zeranol. Thus far, no action has been taken

on Zeranol.

OSHA

Annual Report Chemicals

OSHA regulates exposures to 52 Annual Report chemicals, although for 35 of these chemicals, the standards were based on noncarcinogenic

effects and were adopted as “startup” standards

15 years ago. These standards may not be sufficiently protective when potential carcinogenicity

is considered. OSHA has issued “permanent”

standards based on carcinogenicity for 17 Annual

Report chemicals. Ten of these were part of the

“14-carcinogen standard” issued in 1973, while the

remaining 7 chemicals were regulated individually. One of these, asbestos, has been the subject

of two different “permanent” standards. Two of

OSHA’s permanent standards were overturned by

the courts. One of these (regulation of benzene)

is currently the subject of a new proposal. In the

meantime, however, the old startup standard continues to be used. The other (4,4’ -methylene bis

(2-chloroaniline)) never had a startup standard

and is currently unregulated. New standards have

been also proposed for two more Annual Report

chemicals, formaldehyde and ethylene dibromide

(EDB).

As mentioned above, OSHA is also using the

Annual Report as part of its hazard communication standard. While this information will be valuable to employers and employees, it does not replace the need for standards that set exposure

limits and require controls. OSHA itself is considering regulatory action on several Annual Report chemicals. The actions summarized here are

only OSHA regulatory actions that set exposure

limits or control requirements.
183

While OSHA has exposure standards and requirements, based on either carcinogenic effects

or other toxicities, for 52 Annual Report chemicals, it has no exposure standards of either type

for the other 93 Annual Report chemicals. These

unregulated chemicals and the 35 chemicals with

startup standards based on noncarcinogenic toxicities gives a total of 128 Annual Report chemicals that OSHA does not regulate for carcinogenicity.

Not all of these 128 chemicals are currently

produced or used in the United States. Using the

OTA-defined OSHA jurisdiction (potential

worker exposure detected in NIOSH occupational

surveys or production volume greater than 1 million pounds), 58 of the 93 Annual Report carcinogens lacking standards and 25 of the 35 with

startup standards are of regulatory concern to

OSHA. Thus, the OSHA jurisdiction includes 83

of the 128 Annual Report chemicals that lack

standards based on carcinogenicity.

Considered another way, OSHA has issued

standards based on carcinogenicity for 17 Annual

Report chemicals and noncancer standards for

another 35. Fifty-eight Annual Report chemicals

lacking standards are in the OSHA jurisdiction.

The total OTA-defined jurisdiction is 110 Annual

Report chemicals.

Positive NCI/NTP Chemicals

As mentioned above, OSHA has issued permanent standards related to carcinogenicity for 2 of

the 144 positive NCI/NTP chemicals—asbestos

and 1,2-dibromo-3-chloropropane (DBCP). Neither of these actions, however, was based primarily on the NCI/NTP test results: asbestos is a human carcinogen, and DBCP was regulated by

OSHA primarily because it caused sterility in male

workers, although the NCI carcinogenicity data

were available and were considered by OSHA

when it set the standard.

Two other positive NCI/NTP chemicals have

been proposed for new standards—benzene and

EDB. Benzene had been the subject of a final

standard in 1978 based on human evidence, but

the standard was overturned by the courts. OSHA

issued a proposal for EDB in 1983, but no standard has been issued in final form, although most

pesticide uses of EDB were canceled by EPA in

1984.

EDB has actually been tested twice by NCI/

NTP. The first results, positive in all four experiments using gavage exposure, were published in

1978, while the second results, positive in all four

experiments in an inhalation study, were published in 1982. OSHA still has not issued a standard. In explaining its “cancer policy, ” OSHA described a bioassay result that it should not ignore,

even if the test results were based on high doses:

Those who would urge OSHA to reject data

from tests conducted at “too toxic” doses would

presumably wish OSHA to ignore data such as

those on 1,2-dibromoethane [ethylene dibromide], which induced multiple-site tumors at

both dose levels in both sexes of rats and mice

within 60 weeks of exposure, at incidence rates

up to 94 percent. . . . OSHA believes that it

would be improper to ignore such overwhelming evidence of hazard (274).

This quotation refers to the 1978 NCI results.

Twenty-seven of 144 positive NCI/NTP chemicals (19 percent) are currently regulated under the

OSHA startup standards based on noncarcinogenic toxicity. These include 15 among the 61 with

three or four positive results (25 percent).

Some positive NCI/NTP chemicals are not

present in the workplace in substantial quantities.

As explained above, to develop a jurisdiction of

chemicals of regulatory interest, OTA used information for chemical production and detection in

the NIOSH surveys. Using these criteria, 17 of the

27 positive NCI/NTP chemicals currently regulated with startup standards are of potential regulatory interest to OSHA. Twelve of these have

positive results in three or four experiments. As

mentioned above, proposals are pending for two

of these.

A total of 115 of the 144 positive NCI/NTP

chemicals have no occupational exposure standard. 14 Of the 115 chemicals, 24 are in the OTAdefined OSHA regulatory jurisdiction. Forty-five

“Although positive test results may trigger coverage under standards for labeling and access to medical records.
184

of the 144 positive NCI/NTP chemicals were positive in three or four experiments. Of these, 14 are

in OSHA’S jurisdiction.

Considered another way, OSHA has noncancer

standards for 27 positive NCI/NTP chemicals and

carcinogenicity standards for 2. An additional 24

chemicals were positive in NCI/NTP bioassays

and are in OSHA’S jurisdiction, but have no occupational standard of either sort. Limiting attention to the chemicals that tested positive in three

or four experiments, OSHA has noncancer standards for 15 chemicals and a carcinogenicity standard for 1 more. An additional 14 chemicals with

three or four positive results are in OSHA’S jurisdiction, but have no OSHA standards.

NIOSH

Annual Report Chemicals

NIOSH has prepared recommendations to

OSHA for 59 Annual Report chemicals. For 18

of these, OSHA has issued standards based on

carcinogenicity, although two of these standards

were struck down by the courts (those for benzene and 4,4’-methylene bis (2-chloroaniline)).

OSHA has proposed a new standard for benzene

and for two additional Annual Report chemicals

on which there are NIOSH recommendations (formaldehyde and EDB). In all, there are 20 chemicals with NIOSH recommendations for which

OSHA has either proposed or issued standards

for carcinogenicity. The remaining 39 chemicals

include 24 covered by startup standards, which

as already mentioned, were not based on carcinogenicity, and 15 currently lacking an OSHA

standard.

NIOSH has not issued recommendations for 86

Annual Report chemicals. In this case, once again,

not all of these chemicals are produced or present

potential worker exposures. Based on the OTAdefined jurisdiction, 53 of the 86 chemicals lacking NIOSH recommendations are produced in

quantities greater than 1 million pounds or were

detected in the NIOSH occupational surveys and

thus may present worker exposures.15

150TA defined the NIOSH jurisdiction to include chemicals detected in NIOSH’S occupational surveys as well as chemicals with

annual production volume greater than 1 million pounds. The

NIOSH and OSHA jurisdictions differ slightly because there are several chemicals that NIOSH has made recommendations on, but that

do not satisfy any of the criteria for the OSHA jurisdiction.

Positive NCI/NTP Chemicals

NIOSH recommendations cover 31 of the 144

positive NCI/NTP chemicals (22 percent). NIOSH

recommendations cover 13 of the 61 chemicals

that tested positive in three or four experiments

(21 percent). There are 113 positive NCI/NTP

chemicals for which NIOSH has not issued recommendations, including 48 three- and fourpositive results. Thirty-one of the 113 positive

NCI/NTP chemicals and 22 of the 48 chemicals

with positive results in three or four experiments

are in the OTA-defined jurisdiction for NIOSH.

CPSC

Annual Report Chemicals

CPSC reported regulatory activity or voluntary

control for 18 Annual Report chemicals. These

include four chemicals banned from consumer

products—carbon tetrachloride, tris(2,3-dibromopropyl)phosphate (tris), certain uses of asbestos,

and vinyl chloride used as an aerosol propellant.

In addition, for asbestos, a proposed ban of use

in consumer hair dryers led to voluntary control.

CPSC attempted to ban urea-formaldehyde foam

insulation (UFFI) to prevent consumer exposures

to formaldehyde from this source. This action was

subsequently overturned by the courts, although

use of UFFI has apparently ceased. In addition,

products containing more than 1 percent formaldehyde must bear a label warning of irritation associated with formaldehyde.

Benzene products were already covered by a

labeling requirement when the issue of their carcinogenicity was raised. After a ban of benzene

in all consumer products (except gasoline) was

proposed, the use of benzene in these products

stopped. Exposures to lead acetate and lead phosphate (listed as Annual Report carcinogens, but

grouped as one chemical) are indirectly regulated

through CPSC limits on lead in paint. For five

dyes related to benzidine and found in artist materials, the hazard was voluntarily reduced. Levels

of six different N-nitroso compounds were restricted in children’s pacifiers.

To define a regulatory jurisdiction, OTA asked

CPSC staff to provide information on the occurrence of Annual Report chemicals in consumer

products. Based on this information, 34 Annual
185

Report chemicals are present in consumer products for which no CPSC regulatory actions have

been taken. Five of these are believed to present

actual or possible consumer exposure—arsenic

and arsenic compounds, chromium and chromium compounds, DEHP, 1,2-dichloroethane,

and thiourea.

Limiting attention to chemicals believed to

present actual or possible consumer exposures or

that CPSC has already acted on yields a total of

24 chemicals in the OTA-defined CPSC jurisdiction. Eighteen of these have been subject to CPSC

regulatory action or voluntary reductions or

controls.

Positive NCI/NTP Chemicals

CPSC has addressed eight positive NCI/NTP

chemicals. Three of these were the focus of some

regulatory activity: tris (four positives) was

banned from children’s sleepwear, benzene (four

positives) was voluntarily removed from consumer products after a proposed ban, and several consumer product uses of asbestos (one positive) were eliminated (through bans and voluntary

actions). But again, all actions on benzene and

asbestos were based on human evidence, not NTP

bioassay results.

Five chemicals were subjects of some voluntary

actions, for one of which a proposed labeling requirement is also pending. CPSC reports manufacturers voluntarily stopped using three different dyes (all yielding two positives) in consumer

products. CPSC convened a chronic hazard advisory panel on DEHP (four positives) to consider

regulatory action, but DEHP was voluntarily removed from children’s pacifiers. CPSC has proposed that methylene chloride (four positives) be

labeled a hazardous substance and has achieved

some voluntary reductions in the use of this chemical in consumer products.

Among the 144 positive NCI/NTP chemicals,

65 are present in consumer products. Among these

65, 13 present what CPSC determines to be “actual or possible” consumer exposure.

Defining the CPSC jurisdiction to be those

chemicals that present actual or possible exposures

or that have been acted on by CPSC yields 14

positive NCI/NTP chemicals. Eight of these have

been the subjects of CPSC regulations or voluntary reductions. Seven of the 61 NCI/NTP chemicals with three or four positive experiments fall

in this CPSC jurisdiction. Four of these have been

the subjects of CPSC regulations or voluntary reductions.

EPA Actions Under the Clean Air Act

Annual Report Chemicals

Six Annual Report chemicals have been listed

as hazardous air pollutants, although the listing

of one (beryllium) was based on noncarcinogenic

effects. Emissions standards have been issued for

five of the six listed (asbestos, beryllium, vinyl

chloride, benzene, and arsenic), although proposed standards for benzene are still pending for

other industries. Coke oven emissions standards

have recently been proposed, but are not yet final. EPA has announced the “intent to list” five

other Annual Report carcinogens: carbon tetrachloride, chloroform, chromium, cadmium, and

ethylene oxide.

OTA defined a regulatory jurisdiction for EPA’s

regulation of hazardous air pollutants using information in the EPA-compiled MHAPPS database. Narrowing the jurisdiction to chemicals currently produced in quantities greater than 1

million pounds, OTA has selected the Annual

Report carcinogens with relatively high vapor

pressures, those greater than 100 mm Hg, and

with vapor pressures between 24 and 100 mm Hg.

The Annual Report carcinogens with relatively

high volatility (vapor pressure greater than 100

mm Hg) are vinyl chloride, acrylonitrile, ethylene

oxide, chloroform, and formaldehyde. One of

these five (vinyl chloride) has been listed and regulated. Ethylene oxide and chloroform have been

placed in the “intent to list” category. EPA has

announced a plan to give local governments responsibility for addressing acrylonitrile exposures.

The Annual Report chemicals with lower volatility (vapor pressure between 24 and 100 mm Hg)

and production greater than 1 million pounds are

benzene, carbon tetrachloride, and 1,4-dioxane.

One of these three chemicals (benzene) has been

listed, and a second (carbon tetrachloride) is in

the “intent to list” category.

The total jurisdiction in this case is 15 chemicals, consisting of the 8 chemicals above and 7
186

others that EPA has listed or has announced an

intent to list. Of the 15, 6 have been listed.

Positive NCI/NTP Chemicals

Two NCI/NTP chemicals have been acted on

under the Clean Air Act, although several more

have been subject of pre-regulatory evaluations.

Two NCI/NTP chemicals have been listed—benzene and asbestos—although both decisions to list

were based on human evidence for carcinogenicity and were made before NCI/NTP test results

were available. For six others, EPA has announced

an “intent to list” (l,2dichloroethane, tetrachloroethylene, chloroform, 1,3-butadiene, trichloroethylene, and methylene chloride).

Chloroform, 1,3-butadiene, methylene chloride, and 1,2-propylene oxide are chemicals within the OTA-defined jurisdiction because they

occur in the MHAPPS database, have a production volume greater than 1 million pounds, and

have a vapor pressure greater than 100 mm Hg.

EPA has announced an intent-to-list decision for

three of these four chemicals. NCI/NTP chemicals produced in volumes greater than 1 million

pounds, but with lower vapor pressures (between

24 and 100 mm Hg) are benzene, 1,4-dioxane,

ethyl acrylate, trichloroethylene, l,2-dichloropropane, and 1,2-dichloroethane. Regarding these six

chemicals, EPA has listed one, and announced its

intent to list another.

Considering these chemicals along with those

EPA has already listed or those it has announced

its intent to list, and eliminating the double counting, yields a jurisdiction in this case of 12 positive NCI/NTP chemicals. Two of these have been

listed. Limiting attention to positive NCI/NTP

chemicals with three or four positive experiments,

the jurisdiction is eight chemicals, of which one

has been listed.

EPA Actions Under the

Clean Water Act

Annual Report Chemicals

Under the Clean Water Act, water quality criteria documents have been issued for 47 Annual

Report chemicals. During the 1970s, toxic effluent

standards were issued for five of these chemicals.

But, as discussed in chapter 3, the “Flannery decree” replaced EPA development of toxic effluent

standards with the use of technology-based effluent limitations, which are now used to regulate chemicals covered by the water quality criteria documents. In addition, discharges from the

rubber industry (an Annual Report “chemical”)

are also regulated, although there is no specific

water quality criteria document for this industry.

Beyond these 48 regulated chemicals, EPA’s

database shows that another 17 chemicals detected

in effluent streams have not been regulated. Thus,

the OTA-defined jurisdiction for the EPA clean

water program is 65 chemicals.16

Positive NCI/NTP Chemicals

Water quality criteria documents under the

Clean Water Act that consider carcinogenicity

cover 14 chemicals from positive NCI/NTP bioassays, 7 with three- and four-positive results.

Toxic effluent standards were issued for two of

these chemicals—p,p’-DDE (related to DDT) and

Toxaphene—although both actions took place

prior to publication of NCI/NTP test results. All

14 chemicals are covered by technology-based

standards because they are included in the list of

65 chemicals under the Clean Water Act.

In addition to the 14 positive chemicals covered by water quality criteria documents, EPA’s

database of chemicals detected in effluent streams

shows another 13 positive NCI/NTP chemicals

that have not been regulated. These include two

chemicals with four positives, one with three positives, seven with two positives, and three with

one positive. Thus, the OTA-defined jurisdiction

of positive NCI/NTP chemicals for the clean

water program includes a total of 27 positive test

results. Fourteen of these 27 (52 percent) are covered in the water quality criteria documents that

have been issued to date.

16BY coincidence, this equals the number of classes of priority Pollutants. But the actual overlap is limited to 47 chemicals plus the

rubber indust~.
187

EPA Actions Under the

Safe Drinking Water Act

Annual Report Chemicals

Annual Report chemicals regulated in some

way under the Safe Drinking Water Act include

seven covered by interim standards: arsenic, cadmium, chromium, lead compounds (lead acetate

and lead phosphate17), Lindane, Toxaphene, and

chloroform. The first four of these, however, were

not regulated for carcinogenic effects.

In the current process of setting standards, 11

Annual Report chemicals have been the subjects

of proposed recommended maximum contamination levels (RMCLs): six standards were based on

carcinogenicity for DBCP, EDB, Epichlorohydrin,

Lindane, PCBs, and Toxaphene), while the remaining five were not (for arsenic, asbestos, cadmium, chromium, and lead compounds). For four

more Annual Report carcinogens final RMCLs

and final maximum contamination levels (MCLs)

have been issued: benzene, carbon tetrachloride,

1,2-dichloroethane, and vinyl chloride.

For 19 Annual Report chemicals, EPA has issued health advisories. Of these chemicals, 14

are covered by interim standards or the current

RMCL/MCL process. For the remaining five

chemicals (1,4-dioxane, ethylene thiourea, hexachlorobenzene, nickel, and 2,3,7,8-tetrachlorodibenzo-p-dioxin), only the nonbinding health advisories have been issued.

To define a regulatory jurisdiction, OTA requested that the EPA Office of Drinking Water

Standards indicate which Annual Report chemicals are found in drinking water and which present

significant exposures. The office indicated that 120

of the chemicals in the Annual Report had been

detected in drinking water. Of these, 31 were estimated to present significant human exposures, including 9 of the 10 polycyclic aromatic hydrocarbons. Finally, for eight Annual Report chemicals,

information is inadequate to judge the magnitude

of human exposure.18

EPA has interim standards in place for 7 of the

120 chemicals detected in drinking water. Fifteen

18These chemicals were not included in the OTA-defined jurisdiction.

chemicals are included in the current RMCL/MCL

process. For 18 chemicals, health advisories have

been prepared, although the health advisory represents the only EPA action on 5 of those chemicals in drinking water. These actions cover 21

chemicals altogether; all but one of these were estimated to present significant human exposure. 19

There has been no EPA action on drinking

water exposures for the remaining 99 chemicals.

Of these, 11 chemicals (beryllium, 2,4,6-trichlorophenol, and 9 of the 10 polycyclic aromatic hydrocarbons) were estimated to present significant

known or potential human exposures.

OTA’s jurisdiction for actions under the Safe

Drinking Water Act consists of the 21 chemicals

covered by interim standards or the current

RMCL/MCL process and 11 additional chemicals

with known or potential exposures in drinking

water. Of these 32 Annual Report chemicals, 7

have interim standards, 15 are being considered

in the RMCL/MCL process, and 11 have not been

addressed by regulatory action.

Positive NCI/NTP Chemicals

Twelve positive NCI/NTP chemicals are addressed by either the interim standards under the

act or the current RMCL/MCL standard-setting

process. The two interim standards covered toxaphene (in 1975) and chloroform (in 1979). Eleven

positive NCI/NTP chemicals are addressed by the

current RMCL/MCL process: for three, final

RMCLs and final MCLs have been issued; for one,

a proposed MCL is pending; and for seven, proposed RMCLs are still pending. (Regulatory standards and proposals cover a total of 12 chemicals

because chloroform is not now being addressed

by the RMCL/MCL process. )

Fourteen of the positive NCI/NTP chemicals

are found in drinking water and have been subjects of health advisories. Four of these chemicals

have standards or proposed RMCLs. Thus 10

positive NCI/NTP chemicals found in drinking

water are addressed by health advisories, but not

by the standards-setting process,

19The exception is 2,3, 7,8-tetrachlorodibenzo-p-dioxin.

63-986 0 - 87 - 6
188

EPA staff indicated to OTA that another 24

positive NCI/NTP chemicals are found in drinking water, but in their judgment, 22 are not significant or data are not available on them. The

two with a significant known or potential presence in drinking water that are also not addressed

by the standards-setting process or health advisories are 2,4,6-trichlorophenol (three positives)

and di-(2-ethylhexyl) -adipate (two positives).

The OTA-defined jurisdiction in this case includes only those chemicals EPA has acted on or

that present significant potential drinking water

hazards. Thus, the jurisdiction with regard to

positive NCI/NTP chemicals consists of 14 chemicals. Of these, 2 are addressed by interim standards, 11 by current regulatory activity, and 2 by

no action .20

EPA Actions Under the Federal

Insecticide, Fungicide, and

Rodenticide Act

Annual Report Chemicals

Twenty-four Annual Report chemicals are or

were registered as active pesticide ingredients under FIFRA.21 Thirteen of these are listed as “pesticides” in the Annual Report; the remaining 11

substances are listed in other categories but have

or had pesticide uses. The 24 chemicals include

6 that were voluntarily canceled for some or all

uses (acrylonitrile, Aramite, arsenic, benzene, Kepone, and Safrole).22 Another eight were subject

to complete or partial cancellation by EPA (Amitrole, carbon tetrachloride, DDT, DBCP, EDB,

Mirex, Toxaphene, and vinyl chloride), and five

were subject to special review but were not canceled or suspended (cadmium, chloroform, ethylene oxide, and Lindane). For Nitrofen and sulfallates, EPA has only set food tolerances. Food

tolerances are also reported for six other Annual

Report pesticides. A registration standard has

been issued for formaldehyde.

Zoone chemical is addressed by both interim standards and current regulatory activity.

ZITwelve A~ual Report chemicals are used as inert ingredients

in pesticide formulations. In 1987, EPA announced a policy covering some of these inert ingredients (see ch. 3).

ZZNon.Lindam isomers of hexachlorocyclohexane were also voluntarily canceled, although Lindane itself is still marketed.

No actions are reported for three chemicals used

as active pesticide ingredients: 2,4,6-trichlorophenol, hexachlorobenzene, and l,2-dichloroethane. The Annual Report, however, suggests that

2,4,6-trichlorophenol is no longer being produced

because of the expense of removing dioxin contamination.

Positive NCI/NTP Chemicals

Twenty-seven positive NCI/NTP chemicals are

or were used as active ingredients in pesticides:

seven with four positive results, four with three

positives, six with two positives, and five with

one positive. NTP has also tested DDE, which is

associated with DDT, and which yielded two

positive results, for a total of 28 positive NCI/

NTP chemicals.23

For about half of these chemicals some uses

have been suspended, canceled, or voluntarily

canceled, although nearly all of these chemicals

remain on the market for at least some uses. EPA

has canceled or suspended nine chemicals: DBCP

(four positive results), EDB (four positive results),

Chlordane (two positives), Heptachlor (two positives), chlorobenzilate (two positives), p,p’-DDE

(a contaminant and metabolize of DDT) (two positives), propylene dichloride (two positives), Toxaphene (two positives), and Aldrin (one positive),

Two of these (Chlordane and Heptachlor) are

closely related chemically; EPA acted on them

simultaneously. In addition, four chemicals were

voluntarily canceled as active ingredients: benzene (four positive results), Chlordecone (Kepone)

(four positives), Nitrofen (three positives), and

Monuron (one positive). Of these 13 chemicals

affected by regulatory and voluntary cancellations

and suspensions, a number remain on the market for some uses. For example, Chlordane was

canceled for food uses, but is still used for termite control.

The 15 remaining positive NCI/NTP chemicals

are still on the market with their uses unchanged

by suspension, cancellation, or voluntary cancellation. For one of these chemicals, Tetrachlorvinphos (three positives), EPA judged that the weight

2JThere are also la positive NCI/NTIJ chemicals that are used as

inert ingredients, including 2 that are or were used as active ingredients.
189

of the evidence does not support regulation. Several of the other chemicals have been subjects of

special reviews or registration standards and two

have been proposed for cancellation (Captan and

Dicofol). To some extent, EPA has issued requirements for labeling and use of protective equipment with these chemicals, but OTA did not evaluate these measures.

EPA Actions Under the Toxic

Substances Control Act

Annual Report Chemicals

Under TSCA, 32 of the 145 Annual Report

chemicals have received some attention. Most of

this attention has consisted of developing information, including reporting requirements and

Chemical Hazard Information Profiles (CHIPS).

Under section 8, EPA can issue regulations requiring manufacturers to provide information on production, uses, exposures, environmental and

health effects, and disposal of chemicals (sec. 8(a))

and requiring manufacturers to submit unpublished health and safety studies (sec. 8(d)) .24

CHIPS are medium-sized reviews (e.g., 20 to 70

pages) of physical properties, production and exposure information, health effects, environmental

effects, and other existing standards and regulations for particular chemicals.

Eighteen Annual Report chemicals are subject

to section 8(a) or 8(d) reporting rules. EPA has

prepared CHIPS for 10 other chemicals: benzotrichloride, hydrazobenzene, Michler’s base,

5-nitro-o-anisidine, o-toluidine, 1,4-dioxane, 2-

nitropropane, thiourea, thorium dioxide, and

toluene diisocyanate (TDI). The first five of these

chemicals are used in manufacturing dyes, while

1,4-dioxane and 2-nitropropane are used as solvents. The remaining three chemicals are classed

as miscellaneous chemicals and industrial

chemicals.

EPA has issued final regulations banning production under section 6 for one Annual Report

carcinogen —PCBS. As described in chapter 3,

Congress specified this action under TSCA. A section 6 proposal on asbestos is pending. This proposed regulation would limit and eventually eliminate the use of asbestos.25 For two other Annual

Report chemicals–formaldehyde and MDA–

EPA has initiated an expedited review under section 4(f) and then referred regulatory consideration to OSHA. EPA has issued significant new use

rules for two Annual Report chemicals: hexamethylphosphoramide and urethane.

As defined by OTA, the TSCA jurisdiction consists of all chemicals in the Annual Report, although regulatory action under TSCA would differ depending on whether or not a chemical is

produced. According to the information available

to OTA, domestic production of 47 Annual Report chemicals exceeds 1 million pounds. Another

66 chemicals are produced, but in quantities less

than I million pounds, 13 chemicals are currently

not produced, and the production status of 19

chemicals is unknown.

Narrowing attention to just those Annual Report chemicals produced in quantities greater than

1 million pounds yields 6 chemicals with EPAprepared CHIPS and 11 chemicals subject to section 8(a) or 8(d) reporting rules. The section 4(f)

designations, significant new use rules, and the

section 6 proposal on asbestos (mentioned above)

all affect chemicals drawn from this high-production group. After eliminating multiple actions on

the same chemical, there are 20 high-production

chemicals addressed by some action and 27 highproduction chemicals on which no action has been

taken.

Under TSCA, for chemicals currently not produced EPA could require manufacturers to report

significant new uses or provide production or exposure information prior to restarting production.

Of the 145 carcinogens in the Annual Report, 13

chemicals are not currently produced. Because of

24sec. g(e) of TSCA requi~es manufacturers h report to EPA ‘formation on chemicals that present a “substantial risk of injury to

health or the environment.” While processing these reports has been

an important TSCA activity, it is not directly regulatory and its

purpose is to aid in identifying new hazards. This analysis discusses

chemicals already identified as carcinogenic in the Annual Report

or by NCI/NTP tests.

ZSIn addition, EpA has issued a regulation concerning certain State

and local government employees exposed to asbestos during removal

operations, but whose working conditions are not regulated by

OSHA or the States. This standard is similar to the asbestos standard issued by OSHA for other workers.
190)

the congressional ban, PCBs are among these

chemicals. The remaining 12 chemicals have no

TSCA reporting requirements.

Positive NCI/NTP Chemicals

Three NCI/NTP chemicals have been reviewed

under section 4(f) of TSCA: MDA, 1,3-butadiene,

and methylene chloride. Methylene chloride and

MDA had four-positive results in the NCI/NTP

tests, while 1,3-butadiene showed two positives.

However, 1,3-butadiene had already been shown

to be carcinogenic in rats and thus NTP tested in

mice only. Including the positive rat data would

give this chemical a four-positive result as well.

The NTP test results for these chemicals led

directly to TSCA activity. EPA has referred consideration of formaldehyde, 1,3-butadiene, and

MDA to OSHA under section 9 of TSCA.

One positive NCI/NTP chemical, asbestos, has

been proposed for regulation under section 6. Although the NTP tests found some evidence for

carcinogenicity in male rats (one positive), the primary basis for all asbestos regulation is the human epidemiologic data. 26 EPA has also issued a

significant new use rule for pentachloroethane

(two positives).

Most of TSCA activity on existing chemicals

tested by NCI/NTP has involved reporting requirements under section 8 of TSCA and the preparation of TSCA evaluation documents. The development of this information should be helpful

to any future regulatory activity.

OTA considers all the positive NCI/NTP chemicals to be in the TSCA jurisdiction. Section 8(a)

or 8(d) rules have been issued or CHIPS prepared

for 53 of the 144 positive NCI/NTP chemicals .27

Twenty-two of the 61 chemicals with four-positive

and three-positive results have been the subjects

of section 8(a) or 8(d) reporting rules or CHIPS.

28

26Rules concerning manufacture and disposal of PCBS have also

been issued under sec. 6. However, this action occurred because of

congressional directive. The NCI/NTP test results for Arochlor 1254

(a PCB) were negative.

ZTThese inc]ude 22 sec. 8(a) or 8(d) rules and 37 CHIPS. lle total

is 53 because not all of the chemicals are covered by both.

ZsThese include 11 chemicals subjected to 8(a) or 8(d) rules and

17 chemicals with CHIPS.

EPA Actions Under the Resource

Conservation and Recovery Act

Annual Report Chemicals

Compared to the regulation responses of other

agencies to the Annual Report list, those of RCRA

and CERCLA are the most comprehensive, although their corresponding programs do not address a number of Annual Report chemicals.

Two lists of chemicals are important for the

RCRA program: a list of hazardous wastes (which

lists commercial chemicals and waste streams) and

a list of hazardous constituents of listed wastes

(Appendix VIII of RCRA). The RCRA hazardous

waste list currently includes 89 Annual Report carcinogens, while Appendix VIII includes 18. Because 10 chemicals are on both lists, the number

of chemicals covered by the two lists together is

97. An additional 20 Annual Report chemicals,

not included in either list, are proposed for inclusion in the list of hazardous wastes and 1 (iron

dextran complex) is proposed for removal.

The RCRA lists should be prospective, allowing for the possibility that toxic chemicals currently not produced might be produced in the future and need to be disposed of safely. Therefore,

as defined by OTA, the jurisdiction for RCRA

consists of all chemicals in the Annual Report,

whether or not they are currently produced.

The two RCRA lists currently include 97 of the

145 chemicals in the Annual Report; 48 Annual

Report chemicals are not included. Some of the

48 Annual Report chemicals not listed under

RCRA are not currently produced commercially

—4 according to the SRI data reported in HSDB.

Another six Annual Report chemicals were not

found in HSDB or did not have production data

reported and some of them may also not be produced. Thus, 38 Annual Report chemicals are

produced but not included in the RCRA lists. Nine

of these are produced in quantities greater than

1 million pounds.

Positive NCI/NTP Chemicals

Of the 144 positive NCI/NTP chemicals, 41 appear in either one of the RCRA lists (or both),

while 103 positive NCI/NTP chemicals do not.
191

Limiting attention to chemicals testing positive in

three or four experiments, or 61 chemicals, 39

chemicals (64 percent) have not been listed. Nineteen of the 103 positive NCI/NTP chemicals not

included in the RCRA lists are not currently produced. Twenty-six chemicals were not found in

HSDB or had no reported production data, and

some of these may also not be produced. Fiftyeight of the 103 positive NCI/NTP chemicals are

produced but not included in the RCRA lists. Sixteen of these are produced in quantities greater

than 1 million pounds.

EPA Actions Under the

Comprehensive Environmental

Response, Compensation, and

Liability Act

Annual Report Chemicals

The CERCLA list includes 95 Annual Report

carcinogens, most of which RCRA also lists as

hazardous wastes. Chemicals that were only included in RCRA Appendix VIII have not been incorporated in the CERCLA list, although EPA has

issued an Advance Notice of Proposed Rule Making requesting comments about including them.

Activities under CERCLA may need to assess

the hazards of chemicals no longer produced, but

found in waste dumps from past production.

OTA has not developed any information on

which Annual Report chemicals have been found

in dump sites or have been released into the environment.

29 The OTA-defined jurisdiction for

CERCLA consists of all the chemicals in the Annual Report, whether or not they are currently

produced.

Fifty of the 145 Annual Report chemicals are

not included in the CERCLA list. Examining the

chemicals currently produced in quantities greater

than 1 million pounds yields nine not covered

under CERCLA.

29EPA has recently published a list of 100 hazardous substances

most commonly found at cleanup sites and which will be the subjects of toxicologic profiles required by sec. 110 of the 1986 Superfund amendments (302).

Positive NCI/NTP Chemicals

Of the 144 positive NCI/NTP chemicals, 47,

or about one-third, are included in the CERCLA

list. Two-thirds of the positive NCI/NTP chemicals (94) are thus not included. Of the 61 chemicals with three or four positive experiments, 22

are listed and 39 are not.

EPA recently proposed to adjust, based on evidence of carcinogenicity, the reportable quantities (RQs) for chemicals on its CERCLA list. (The

EPA method for this is described in ch. 3.) The

proposed adjustments do not add chemicals to the

list, but change the RQ based on the classification of a chemical as a high hazard, medium hazard, or low hazard with regard to carcinogenicity. The 47 chemicals on the CERCLA list should

thus be affected by the proposed adjustments.

Only 32, however, are actually included in the

list of chemicals evaluated for these adjustments.

The 15 positive test result chemicals on the

CERCLA list, but not evaluated for carcinogenicity, include several major industrial chemicals:

methylene chloride, 1,2-propylene oxide, ethyl

acrylate; 1,3-dichloropropene (Telone II), and

TDI.

Assessments by EPA’s Carcinogen

Assessment Group

Annual Report Chemicals

CAG has prepared health assessments for 78

Annual Report chemicals. While selection of

chemicals for CAG assessment depends on the

needs of other programs within EPA, 67 of the

chemicals and exposures listed in the Annual Report have not been covered by CAG’s health

assessments. These chemicals include 14 produced

in quantities greater than 1 million pounds.

Positive NCI/NTP Chemicals

In all, CAG has conducted 22 assessments of

the 144 positive NCI/NTP chemicals: 6 chemicals

with four-positives, 3 with three-positives, 11 with

two-positives, and 2 with one-positive. Grouping chemicals with four-positive and three-positive

results together, the NCI/NTP test results cover
192

61 chemicals. CAG has prepared full assessments been regulated or evaluated by any agency. These

for nine of these, or about 15 percent.30 include 13 with four-positive results, 10 with

three-positives, 12 with two-positives, and 8 with

No Apparent Activity one-positive result. None of these chemicals is produced in a quantity greater than 1 million pounds.

Positive NCI/NTP Chemicals Ten are produced in quantities of less than 1 milBased on information available to OTA, 43

lion pounds, 15 are not commercially produced,

positive NCI/NTP chemicals appear not to have and the production status of 18 is unknown.

30As ju5t dims~d,CXG has also conducted analyses of available information for adjusting the CERCLA reportable quantities

based on carcinogenicity.

AGENCY COMMENTS

In comments on a draft of this background paper, officials of Federal regulatory agencies emphasized their belief that they have acted appropriately in regulating the chemicals tested by

NCI/NTP and the Annual Report. They pointed

out that their statutes require that they assess risks

and benefits of using chemicals, as well as the

technical feasibility and costs of regulatory action.

Agency responses to information on carcinogenicity sometimes involve requiring additional information enabling the agencies to make better

decisions. In some cases, the agencies have decided

that regulation is not necessary because a substance is no longer produced, does not present exposures, or the benefits of continued use exceed

the risks. They stated that identification of a

chemical as carcinogenic does not imply a need

for regulation. EPA commented:

SUMMARY

The Annual Report on Carcinogens is a useful

compendium of information on carcinogenic

chemicals, including its coverage of the uses of

these chemicals and related regulatory actions.

The NCI/NTP test results are useful for risk

assessments of particular chemicals. Together, the

NCI/NTP tests provide information useful for further development of risk assessment methods and

exploration of topics in hazard identification.

Such information has a research value in addition to its potential regulatory uses.

Our decision rules are just not so simple. Also,

as the report basically tallies regulations and cannot readily assess decisions not to regulate, a biased picture emerges of the extent to which the

Federal government has acted on carcinogens

(104).

FDA commented:

We believe that FDA has acted responsibly

and appropriately with regard to chemicals identified as carcinogens. Each purported carcinogen

under the Agency’s purview has been evaluated,

and a determination of the appropriate course

of action has been made, There is no backlog

awaiting Agency review. Since many of the substances required no regulatory action, the Agency has made no formal public statements regarding those decisions (24).

Table 5-3 summarizes the number of Annual

Report chemicals and positive NCI/NTP chemicals acted on by each agency and program as well

as the corresponding number of chemicals determined to be in the OTA-defined jurisdiction .31

These tables separate the chemicals discussed in

31TW0 tabl=inapp.B ]istthe chemicals included in this analysis: table B-1 lists the chemicals that appear in the Annual Report

on Carcinogens; table B-2 lists the chemicals tested by NCI/NTP

and indicates the corresponding level of evidence.
193

Table 5-3.—Agency Actions on positive NCI/NTP chemicals and Annual Report Chemicals—

Actions and Jurisdictiona

Level of evidence

NCI/NTP chemicals

At least one Three and four

positive experiment positive experiments Annual Report chemicals

Actions Jurisdiction Actions Jurisdiction Actions Jurisdiction

No activity . . . . . . . . . . . . . . . . .

CAG assessment . . . . . . . . . . .

RCRA listed or App. Vlll . . . . .

CERCLA

Listed . . . . . . . . . . . . . . . . . . .

Proposed RQ adjust. . . . . . .

CWA WQC or standards . . . . .

SDWA

Interim std. (1975 and 1979)

Proposed and final RMCL . .

Total c 

. . . . . . . . . . . . . . . . .

CAA listed . . . . . . . . . . . . . . . . .

TSCA

Rule 8a or 8d or CHIP . . . . .

4(f) review/SNUR/Sec. 6 . . . .

Total c 

. . . . . . . . . . . . . . . . .

FIFRA

Susp. Cane. . . . . . . . . . . . . . .

Vol. Cane. . . . . . . . . . . . . . . .

Total c 

. . . . . . . . . . . . . . . . .

Food and Cosmetics (Ban,

SUR, or action level) . . . . . .

FDA

Animal drugs

(revoked/withdrawn) . . . . .

Human drugs

(labeled/withdrawn). . . . . .

NIOSH recommendation . . . . .

OSHA

Noncancer std. . . . . . . . . . . .

Cancer std. . . . . . . . . . . . . . .

Total c 

. . . . . . . . . . . . . . . . .

CPSC

Ban/restricted . . . . . . . . . . . .

Voluntary reduction only . . .

Total c 

. . . . . . . . . . . . . . . . .

—

22

41

43

144

144

—

9

22

23

61

61

—

78

97

—

145

145

47

32

14

144

47

27

22

15

7

61

22

10

145

48 65

2

11

12

2

14

14

1

5

6

7

7

7

15

21

6

32

32

12 1 8 15

53

5

56

144

144

22

2

24

61

61

28

6

33

145

145

9

4

13

22

22

2

3

5

11

11

7

5

12

24

24

17 48 7 19 46 52

4 5 1 1 2 6

6

31

12

62

5

13

6

39

26

59

31

112

27

2

29

53

53

15

1

16

30

30

35

17

52

110

110

2

57

8

14

14

1

3

4

7

7

11

8

18

23

23

aJurisdiction refers t. the number of chemicals for which the agency is held responsible Wing the results of OTA’S analysis. (SSS ch. 5).

‘Not determined.

cTotal after eliminating double COunting.

SOURCE: Office of Technology Assessment, 1987

this chapter into three groups: all NCI/NTP chem- ber not acted on for each agency and program

icals with at least one positive experiment, the included in the OTA analysis.

NCI\NTP chemicals with three or four positive

experiments, and the chemicals included in the In general, while a number of regulatory acAnnual Report. Figure 5-1 summarizes these re- tions appear to have been based directly on posisults by presenting graphically the number of these tive NCI/NTP results, there also appear to be subchemicals that have been acted on and the num- stantial gaps in regulatory activity. Considering
194
195

each agency or program individually reveals that

no agency has regulated more than a third of the

positive test results. More typically, an agency

will have acted out of concern for carcinogenicity on 5 to 30 of the 144 chemicals that tested positive in NCI/NTP bioassays.

As described in this chapter, OTA has attempted to focus on the chemicals of potential regulatory interest for each agency or program. However, as shown in table 5-3 and figure 5-1 and as

discussed in this chapter, even when attention is

limited to chemicals in the jurisdiction of the

different agencies and programs, there appear to

be omissions in regulatory coverage. The importance of these apparent regulatory gaps depends

on factors not analyzed by OTA, including the

extent and magnitude of exposures, the potency

of the chemicals, as well as other exposures and

risk factors. In some cases, voluntary industry actions may have reduced or eliminated risks in the

absence of government regulation. OTA has not

determined the extent of these voluntary actions.
Appendixes
Appendix A

Statutory

Regulating

Authority for

Carcinogens

Introduction

By one accounting, 21 different laws may be used

to regulate carcinogens (table A-l). However, this appendix describes only the major statutes providing for

regulation of human exposure to carcinogens, and the

significant judicial decisions affecting this regulation.

Most of the statutes do not single out carcinogens

for specific consideration, but merely regulate them

as a species of toxic substances. A few, however, have

provisions aimed directly at carcinogens; one, the

Food, Drug, and Cosmetic Act (FDCA), has special

statutory provisions for regulating carcinogens as distinguished from other toxic substances, while several

others—the Clean Water Act (CWA), the Toxic Substances Control Act (TSCA), and the Resource Conservation and Recovery Act (RCRA)—mention carcinogens specifically.

Some statutes require premarket review or approval

. .

of a substance before it can enter into commerce. This

requirement is set in parts of FDCA and TSCA, and

in the Federal Insecticide, Fungicide, and Rodenticide

Act (FIFRA). Even for these three laws, however, the

requirement for premarket review applies only to new

pesticides or “new” chemicals being proposed for manufacture, although FDCA requires premarket approval

. .

of new uses for existing chemicals.

A much larger number of statutes, including parts

of FIFRA and TSCA and the other statutes described

in this chapter, provide for postmarked regulation of

substances-after they have been in commerce and people have been exposed to them. Such laws might require an agency to find that there is a health problem

and then propose a regulation based on that-finding,

Table A-1 .—Statutes Authorizing Regulation of Carcinogens

Legislation Agency Area of concern

● Food, Drug, and Cosmetic Act (1906, 1938, amended 1958,

1960, 1962, 1968)

● Federal Insecticide, Fungicide and Rodenticide Act (1948,

amended 1972, 1975, 1978)

Dangerous Cargo Act (1952)

Atomic Energy Act (1952)

● Federal Hazardous Substances Act (1960, amended 1961)

Federal Meat Inspection Act (1967)

Poultry Products Inspection Act (1970)

Egg Products Inspection Act

● Occupational Safety and Health Act (1970)

Poison Prevention Packaging Act (1970, amended 1977)

● Clean Air Act (1970, amended 1974, 1977)

Hazardous Materials, Transportation Act (1972)

● Clean Water Act (formerly Federal Water Control Act) (1972,

amended 1977, 1978)

Marine Protection, Research and Sanctuaries Act (1972)

● Consumer Product Safety Act (1972, amended 1981)

Lead-based Paint Poison Prevention Act (1973, amended

1976

● Safe Drinking Water Act (1976)

● Resource Conservation and Recovery Act (1976)

● Toxic Substances Control Act (1976)

● Federal Mine Safety and Health Act (1977)

● Comprehensive Environmental Response, Compensation,

and Liability Act (1981)

FDA

EPA

DOT, USCG

NRC

CPSC

USDA

OSHA

CPSC

EPA

DOT

EPA

EPA

CPSC

CPSC, HHS, HUD

EPA

EPA

EPA

DOL, NIOSH

EPA

Foods, drugs, cosmetics, and

medical devices

Pesticides

Water shipment of toxic materials

Radioactive substances

Toxic household products

Food, feed, color additives,

pesticide residues

Workplace toxic chemicals

Packaging of hazardous household

products

Air pollutants

Transport of hazardous materials

Water pollutants

Ocean dumping

Hazardous consumer products

Use of lead paint in federal assisted

housing

Drinking water contaminants

Solid waste

Hazardous chemicals not covered

by other acts

Toxic substances in coal and other

mines

Hazardous waste cleanup

“Discussed in this appendix.

SOURCE Office of Sciency and Technology Policy, 1985.

199
200

as in the Clean Air Act (CAA), the Clean Water Act,

the Safe Drinking Water Act (SDWA), and the Occupational Safety and Health Act. Still other laws might

require an agency to find that there is a health problem, establish this fact in court, and seek some judicial remedy on that basis. Some sections of FDCA

require this for foods contaminated by naturally occurring environmental carcinogens.

Except for the few parts of statutes that require

court-ordered remedies, most agencies authorized to

regulate toxic substances causing health problems must

follow procedures mandated by the Administrative

Procedure Act, or similar procedures. In regulating

substances an agency must follow these procedures for

agency “rulemaking” in order to “issue a rule. ” Such

rules may be issued according to rulemaking procedures that range from the relatively informal to the

formal, resembling proceedings in a court of law. In

general, the agency must announce in the Federal Register that it is proposing to regulate a substance (or

group of substances), and describe the nature of the

proposed regulation (5 U.S.C. 553(b)). The agency

must also give interested parties “an opportunity to

participate in the rulemaking through submission of

written data, views, or arguments . . .“ (5 U.S. C.

553(c)). Following the comment period, the agency

usually holds hearings during which interested parties

may have their comments heard. After considering

both written and oral comments, the agency issues a

final rule.

Apart from these common features, informal and

formal rulemaking are distinguished by the nature of

evidence presented during the notice and comment

period and at the hearings, the procedures followed

at the hearing itself, and the standard of judicial review

of agency action. Generally, under formal rulemaking

an agency must conduct quasi-judicial proceedings

with the opportunity to cross-examine witnesses, and

agency decisions following such proceedings are in theory more closely scrutinized by the courts if the regulatory decisions are appealed (103). Under most of the

statutes considered here, the agencies act under the requirements for informal rulemaking.

At least some of the statutes also provide for immediate emergency action, such as immediate suspension under FIFRA or the establishment of Emergency

Temporary Standards under the Occupational Safety

and Health Act.

Finally, in considering the statutes, the reader should

be aware of some differences between the substantive

requirements of the statutes. Different laws reveal

different attitudes toward risk. Some statutes reflect

attitudes quite averse to human health risks posed by

chemical substances. The most extreme example is the

Delaney clause of FDCA. According to that provision,

if a food additive causes cancer in humans or in animal tests, it is declared “unsafe” and is not allowed

as a food additive. The risk to human health is the only

factor taken into account. This is a “no-risk” statute.

Other risk-based statutes use different statutory language. CAA makes risks to human health the primary

factor by setting the goal of regulating with an “ample margin of safety” (42 U.S.C. 7412(a)(2)). Another

approach is risk-risk balancing: weighing the risk to

human health from exposure to a regulated substance

against the risk to human health from not having the

substance in commerce. The FDCA appears to permit

this kind of risk-risk balancing for food additives approved by the Food and Drug Administration (FDA)

prior to 1958 (127). For human drugs, FDA uses a

“risk-benefit” approach, although again, the primary

factor involves the benefits and risks to patient health.

Some statutes are “technology based” laws. These

may require, for example, the agency to reduce emissions from a particular source to the extent this may

be achieved by technological devices placed on the

emitting source. Some such statutes require the “best

practical technology” (BPT) or the “best available technology” (BAT). “Such regulations do not force new

technology, but bring all control efforts up to standards established by existing control technologies” (217).

Other technology-based statutes might be “technology

forcing” because “new techniques may be required to

achieve” some predetermined level of pollutant concentration (217).

Still other statutes permit agencies to balance the

risks to human health from carcinogens against benefits to be obtained by consumers, manufacturers, and

others by permitting the substance to be in commerce.

This is a risk-benefit balancing statute. Congress used

the term “unreasonable risk” in TSCA to refer to this

kind of balancing.

Occupational Safety and

Health Administration

The Occupational Safety and Health Act of 1970

established the Occupational Safety and Health

Administration (OSHA) and the National Institute for

Occupational Safety and Health (NIOSH). OSHA sets

and enforces regulations to control occupational health

and safety hazards, including exposure to carcinogens.

NIOSH is a research agency that has contributed to

the regulation of carcinogens by supporting epidemiologic research and recommending to OSHA changes

in health standards.

The Occupational Safety and Health Act provides

three statutory mechanisms for setting standards to

protect employees from hazardous substances such as
201

carcinogens. Section 6(a) authorized OSHA to adopt

the health and safety standards already established by

Federal agencies or adopted as national consensus

standards. This authority was limited to the first 2

years after the act went into effect (April 1971 to April

1973). An unspecified number of carcinogens were regulated on the basis of their noncarcinogenic effects by

these start-up standards.

Section 6(c) authorizes OSHA to issue emergency

temporary standards (ETS) that require employers to

take immediate steps to reduce workplace hazards. An

ETS may be issued after OSHA determines that employees are exposed to a “grave danger” and that an

emergency standard is “necessary to protect employees from such danger. ” An ETS, issued without opportunity for comments or for a public hearing, goes

into effect immediately. The issuance of an ETS also

initiates the process of setting a standard under section 6(b), with the published ETS ordinarily serving

as the proposed standard. The act mandates that a final standard be issued within 6 months of publication

of the emergency standard.

Finally, section 6(b) authorizes OSHA to issue new

permanent exposure standards and modify or revoke

existing ones by informal rulemaking. However, as a

result of congressional compromise, OSHA’s informal

rulemaking is reviewed by the courts under the “substantial evidence test” normally reserved for formal

rulemaking on the record (190).

OSHA’s rulemaking can result in requirements for

monitoring and medical surveillance, workplace procedures and practices, personal protective equipment,

engineering controls, training, recordkeeping, and new

or modified permissible exposure limits (PELs). Permissible exposure limits are the maximum concentrations of toxic substances permitted in the workplace

air.

From 1971-1986 OSHA issued 23 separate health

standards in 9 regulatory actions after rulemaking.

Eight of OSHA’s final actions on individual health

standards established new PELs and other requirements on carcinogens (asbestos (1972), vinyl chloride,

coke oven emissions, benzene, 1,2-dibromo-3-chloropropane (DBCP), arsenic, acrylonitrile, ethylene oxide, and asbestos (1986)). One OSHA action regulating a group of “14 carcinogens” did not establish a PEL,

but created new requirements for work practices and

medical surveillance for employees exposed to this

group of carcinogens.

Significant Judicial Decisions

OSHA’s regulation of carcinogens has been controversial. Of eight final actions on individual carcinogens, six have resulted in court challenges (asbestos

(1972), vinyl chloride, coke oven emissions, benzene,

arsenic, and ethylene oxide). Only the DBCP and

acrylonitrile regulations were not challenged as final

standards. In addition, there were 3 court challenges

to the group regulation of 14 carcinogens: Dry Color

Manufacturing Association v. Department of Labor

(46) vacated temporary standards for ethyleneimine

and DCB; Synthetic Organic Chemical Manufacturers

Association v. Brennan (191) upheld the permanent

standard for ethyleneimine; and Synthetic Organic

Chemical Manufacturers Association v. Brennan II

(192) vacated the standard for 4,4-methylenebil(2-

chloraniline) MBOCA. OSHA’s rules were upheld for

asbestos (1972), for vinyl chloride, for coke oven emissions, and for arsenic. The courts vacated the temporary asbestos standard in 1984 and the permanent

benzene standard in 1980.

The decisions resolving these disputes have focused

on several major issues. Courts have had to provide

interpretations of 1) the role of the courts in scrutinizing agency actions, and 2) the nature of OSHA’s burden in demonstrating the merits of its standards. In

setting standards the crucial section of the act states:

[OSHA]. . . shall set the standard which most adequately assures, to the extent feasible, . . . that no employee will suffer material impairment of health or

functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life (U. S.C. 655

(b)(5)).

Early decisions by the Courts of Appeal clarified the

courts’ role in reviewing OSHA standards under the

substantial evidence test and the standards of economic

and technological feasibility. OSHA may impose regulations even if doing so means raising standards

above those that exist in the status quo or above those

achievable by present technology (186). In this sense,

OSHA can force the development of new technology.

Similarly, courts have held that although Congress did

not intend to put whole industries out of business to

protect their employees’ health, it did foresee that

health regulations would entail costs and that some

businesses might close (5,98).

In a major decision, the Supreme Court invalidated

OSHA’s 1978 benzene exposure standard. The Court

ruled that the 1 part per million (ppm) exposure limit

was not supported by appropriate findings. A plurality of the Court said that the new standard did not

rest on a finding that exposure to 10 ppm would cause

leukemia while exposure to 1 ppm would not, and that

OSHA acted on assumptions in claiming: a) that exposure to 10 ppm of benzene might cause leukemia and

b) that the number of such cases might be reduced by

lowering the permissible exposure level to 1 ppm (96).
202

According to the plurality opinion, section 3(8) defines occupational health and safety standards as requirements ’’reasonably necessary or appropriate to

provide safe or healthful employment,’’ and requires

OSHA to make a threshold finding that a workplace

is “unsafe” before issuing a standard (96). According

to the plurality, “safe” does not mean risk free, and

a workplace is not “unsafe” unless it it poses a “significant risk of harm” to the worker (96). In addition,

the Court said that “the burden [is] on the Agency to

show, on the basis of substantial evidence, that it is

at least more likely than not that long-term exposure

to [a toxic substance] . . . presents a significant risk

of material health impairment” (96).

This review and interpretation of OSHA’s benzene

standard changed the way OSHA regulates. Prior to

this decision, OSHA had refused to prepare quantitative risk assessments concerning substances it regulated. In proposing subsequent standards, the agency

has had to demonstrate that exposure at the current

permissible levels presents a “significant risk” to workers before it is justified in proposing lower exposure

standards. OSHA now uses a four-step process for

making decisions about health standards:

First, the agency determines that the hazard in question poses a “significant risk . . .“ [as required by the

benzene decision]. Second, OSHA determines that regulatory action can reduce this risk. Third, it sets the

regulatory goal (for health standards, this is the permissible exposure limit) based on reducing this risk “to

the extent feasible.” Finally, OSHA conducts a costeffectiveness analysis of various options to determine

which will achieve this chosen goal in the least costly

manner (219).

In 1981, a second Supreme Court ruling provided

a partial interpretation of “feasibility. ” In opposing

new lower standards on exposure to cotton dust, industry had argued that the Occupational Safety and

Health Act required cost-benefit analysis before OSHA

could issue new standards. The Supreme Court, with

a five-member majority comprised of the four dissenters from the benzene case and the author of the

benzene plurality opinion, Justice Stevens, strongly rejected this claim, arguing that:

Congress itself defined the basic relationship between costs and benefits, by placing the “benefit” of

worker health above all other considerations save

those making attainment of this “benefit” unachievable. Any standard based on a balancing of costs and

benefits by the Secretary that strikes a different balance than that struck by Congress would be inconsistent with the command set forth in section 6(b)(5).

Thus, cost-benefit analysis by OSHA is not required

by the statute because feasibility analysis is (6).

The agency regards this decision as neither requiring

nor permitting the use of quantified cost-benefit analysis for the purposes of setting standards (100,118).

(See (219) for a more detailed discussion of these

issues. )

Recently, a different kind of case has been litigated.

Because of health concerns about employee exposure

to ethylene oxide, the Public Citizen Health Research

Group sued OSHA to issue an ETS. A district court

ruled in favor of Public Citizen and ordered OSHA

to issue such a regulation. On appeal, the District of

Columbia Court of Appeals overruled the district court

judge’s decision on the grounds that he had impermissible substituted his evaluation for that of OSHA.

However, because OSHA had “unreasonably delayed”

acting on ethylene oxide, the court ordered OSHA to

issue a notice of proposed rulemaking within 30 days

of the Court’s decision and a final rule within 1 year’s

time (165).

The Mine Safety and

Health Administration

The Mine Safety and Health Administration

(MSHA) regulates the exposure of miners to carcinogens. The Federal Mine Safety and Health Act Amendments of 1977 consolidated the regulation of mine

health and safety under one statute, and transferred

responsibility from the Department of the Interior to

the Department of Labor. Safety and health in coal

mines had previously been regulated under the Federal Coal Mine Health and Safety Act of 1969 by the

Department of the Interior’s Mining Enforcement and

Safety Administration (MESA). Safety and health in

metal and nonmetallic mineral mines had been regulated by MESA under the Federal Metal and Nonmetallic Mine Safety Act (1966) (150).

As described in Chapter 3, much of MSHA’s regulation of toxic exposures involves incorporating by

reference the lists of standards of a private organization, the American Conference of Governmental Industrial Hygienists (ACGIH). The original intention

was to update these standards automatically whenever

ACGIH issued changes. However, this has not happened. The administration fears violating the Administrative Procedure Act because automatic updates

would not provide an opportunist y for public comment

(190).

How much of a legal difficulty this situation presents

is difficult to know. For example, OSHA’s Hazard

Communication (Labeling) Standard requires that employers provide information to employees on substances to which they are exposed and on the concentrations that are regarded as “not harmful.” According

to OSHA’s regulations employees must be informed

about the most recent ACGIH list of toxic substances

(190).
203

Food and Drug Administration

The Food and Drug Administration regulates foods,

drugs, and cosmetics under FDCA. FDCA is the result of several laws passed by Congress since the first

Federal statute regulating food safety, the Food and

Drug Act of 1906 (127). The Federal Food, Drug, and

Cosmetic Act of 1938 established the general outlines

of current FDA authority. Congress has amended it

with the Pesticides Residue Amendment of 1954, the

Food Additives Amendment of 1958, the Color Additive Amendments of 1960, the Drug Amendment of

1962, and the Animal Drug Amendments of 1968.

Main Statutory Provisions for Regulating

Carcinogens in Foods and Cosmetics

Carcinogens in foods and cosmetics may be and

have been regulated under many different provisions

of FDCA, depending on whether they are considered

food additives, food contaminants, naturally occurring parts of the food, or color additives in foods,

drugs, and cosmetics. In addition, parts of the law

have premarket approval provisions, while others

have postmarked enforcement provisions.

Under FDCA a food is considered to be adulterated,

and thus illegal to sell in interstate commerce, if it contains a food or color additive that is unsafe. An additive is regarded as unsafe if it “may be injurious to

health” or is “ordinarily injurious to health” according to section 402(a)(l) (21 U.S. C. 342(a)(2)(c)); if it

contains any added poisonous or deleterious substance

that is unsafe according to section 406 (21 U.S, C.

342(e); 21 U.S. C. 346); if it contains a food additive

which is carcinogenic according to the Delaney clause

(sec. 409) (21 U.S.C. 348(a)); or if it contains a color

additive that is carcinogenic according to the Delaney

clause for color additives (21 U.S.C. 376(a)).

The Delaney Clause for Foods, Section 409.-In the

Food Additives Amendment of 1958, Congress established a premarket approval procedure for food additives (127). This amendment contains the well-known

“Delaney clause, ” named after Rep. James Delaney of

New York, whose hearings led to the amendment

(127).

According to FDCA, foods may not contain any intentional additive unless FDA has established conditions under which the additive may be safely used (the

general safety provision of section 409) or has issued

an exemption from this requirement, The Delaney

clause applies to this process of approving the safe use

of food additives and provides:

. . . that no additive shall be deemed to be safe if it

is found to induce cancer when ingested by man or

animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal . . . (21

U.S.C. 348(c)(3)(a)).

Thus, if appropriate evidence indicates that a food additive is carcinogenic, FDA may not consider it safe

and must prohibit its use in food. 1 The manufacturer

has the burden of proving that food additives are safe

before they receive approval to enter the market.

Food additives that are carcinogenic but that have

previously been approved by FDA or the U.S. Department of Agriculture, or that are generally recognized

as safe (GRAS) (because they were commonly used in

food at the time the Delaney clause was passed or are

generally recognized by experts as safe on the basis

of toxicological tests), are not regulated under section

409. They are instead subject to section 402(a)(l) (127).

Provisions for color additives (21 U.S. C. 376) are

similar to section 409 provisions for food additives,

i.e., carcinogenic color additives are to be prohibited

by FDA.

Although section 409 condemns food additives that

are carcinogens, the agency, in an advance notice of

proposed rulemaking (ANPR), has indicated an intention to rely on the general safety provision of section

409 rather than the Delaney clause for additives that

contain carcinogens. In its 1982 ANPR, following the

Kennedy v. Monsanto decision in 1979 (described below), the agency proposed that food and color additives that, taken as a whole, do not cause cancer in

animals, but do contain small amounts of carcinogenic

impurities should fall under the general safety clause,

not the Delaney Clause. If the additive itself is not

found to be harmful as shown by quantitative risk

asessment procedures, then it is considered safe even

though it contains carcinogenic impurities. The FDA

impurities policy was upheld in the Scott v. FDA decision. Previously FDA had used the policy on a caseby-case basis for a number of food and color additives,

including some color additives that are not ingested

(245).

General Provision Concerning Food Adulteration

(Section 402(a) (l)).—Section 402(a)(l) declares that a

food is adulterated if it contains added substances that

“may render it injurious to health, ” or if it contains

any substance, added or not, that would “ordinarily

render it injurious to health” (21 U.S. C. 342(a)(l))

(1982), The latter standard includes substances that are

naturally occuring food constituents (127). The difference between the two is that the first is more stringent,

permitting FDA to establish its case with a lower prob-

‘There are three different versions of the Delaney clause, the one described

above for food additives, one enacted at the same time for drugs fed to animals, and one enacted in the Color Additives Amendments of 1960. While

they differ in detail, they all prohibit animal and human carcinogens,
204

ability of risk. The first allows consideration of sensitive populations, while the second does not (128).

If FDA determines a food to be adulterated under

either of these two clauses, it must go to court to remove the food from the market (127). In such a case

FDA, not the manufacturer, has the burden of locating the contaminated food, analyzing its chemical

makeup, and proving that the substance is harmful

(127).

Unavoidable/Necessary Contaminants (Sections 406

and 402(a) (2)( A)).—Under sections 406 and 402(a)

(2)(A), FDA is permitted to set tolerance limits for “unavoidable contaminants and other poisonous or deleterious substances that may be necessary aspects of

food production” (127). These sections are used primarily for unavoidable contaminants of food such as

aflatoxins in peanuts, mercury in fish, and PCBs in

milk and fish (127). Together, sections 402(a)(2)(A)

and 406 declare a food adulterated if it contains any

added poisonous or deleterious substances except

where they cannot be avoided or are required in the

production of food. In this case, FDA may set tolerance levels for the protection of public health, and the

food will be considered safe unless the tolerances for

the added substances are exceeded (21 U.S.C. 348).

Tolerances must be established by means of the most

extreme version of formal rule making procedures

(127). Foods that have levels of contaminants exceeding such tolerances are subject to postmarked judicial

seizure under section 402(a)(2)(A).

Several considerations enter into the FDA’s tolerance setting:

● the level of a contaminant not posing a risk to

health,

● the ability of good manufacturing practices to reduce concentrations,

● analytical capabilities for detecting the contaminant, and

Ž the value of the food (127).

This section was not used until the mid 1970s, but since

has been used to establish tolerances for some unavoidable environmental food contaminants (127). Even the

tolerance setting provisions have not been widely used

because they involve formal rulemaking. Thus, for

most foods which might fall under sections 406 and

402(a)(2)(A), the agency has instead merely set “action levels” for contaminants: levels that, if exceeded,

would lead the agency to bring court action to seize

the food.

Section 408 provided FDA with authority to regulate pesticide residues on raw agricultural products,

but this authority was transferred to EPA in 1970. The

regulation of pesticide residues will be discussed under the regulation of pesticides.

The several categories of food constituents and color

additives that are regulated under the authority of

FDCA are summarized in table A-2.

The Regulation of Animal Drug Residues

Animal drug residues and animal feed additives that

leave residues in human foodstuffs are subject to the

Delaney clause, but with a qualification. Originally,

animal drug residues were subject to the Food Additives Amendment of 1958, with its Delaney clause. In

1962, however, Congress amended FDCA to permit

carcinogenic residues in animal tissues as long as the

residues are in lower concentrations than those that

it has set as safe and detectable by FDA-approved analytic techniques. If carcinogenic residues exceed FDAspecified levels, they are subject to the Delaney clause.

The Regulation of Drugs With

Carcinogenic Potential

FDA evaluates both new and previously approved

drugs. New drugs require premarketing approval, subject to risk-benefit considerations:

A drug is approved only if the benefits are judged

to exceed the risks (real and potential) under intended

conditions of use. For drugs, vaccines, medical devices,

and diagnostic aids, the term “safety” is never treated

as an absolute but is thought of as inherently involving a weighing of benefit and risk (233).

In the approval process an applicant must submit two

kinds of application: an Investigative New Drug (IND)

application (an application to conduct an investigation into a new drug), and then a New Drug Application (NDA) (an application to conduct a more detailed

investigation into a new drug). (For a more detailed

discussion of this approval process see (218).)

An applicant first submits an IND application. FDA

has 30 days to consider whether the preclinical investigations suggest an undue risk to research subjects that

would preclude initiation of human studies. At any

time during the research period FDA can terminate the

research. In 1983, the Agency received approximately

2,000 IND applications (233). An initial IND application normally would include “chemical, manufacturing, and control information; pharmacologic and toxicologic information from animals and in vitro

systems; a plan of clinical study . . .“ (233). Animal

carcinogenicity tests are required for marketing approval of drugs that would be administered chronically or intermittently in a large population (see discussion in ch. 2).

After the research period an applicant submits an

NDA (data developed during the IND-NDA process).

An NDA must include full reports of toxicological
205

Table A-2.— Foods and Drugs Regulated Under the Food, Drug, and Cosmetic Act

Category Description Applicable statutory scheme

A. Direct food additives

1. Ordinary food additives

2. Substances generally

recognized as safe (GRAS)

3. Substances previously

sanctioned by FDA or USDA

B. Color additives

C. Indirect constituents of food

1. Indirect food additives

2. Animal drug residues

3. Pesticide residues

D. Natural food constituents

E. Unavoidable “added”

constituents of food

Substances intentionally added to

processed foods

Substances used in foods prior to 1958

or substances recognized by experts

as safe based upon toxicological

tests

Intentionally added food constituents

previously sanctioned by either FDA

or USDA

Substances used to color foods, drugs,

and cosmetics

Substances used in proximity with

food in ways that may permit small

amounts to migrate and to become

part of the food, e.g., substances

used in packaging or in equipment

used to process or store food

Compounds administered to foodproducing animals as drugs or feed

supplements

Residues of pesticides on raw agricultural products or in processed

agricultural products

Naturally occurring food constituents,

e.g., oyster shell fragments,

mushrooms, and mussels (not

known as carcinogens)

Substances not inherent in agricultural

commodities which may unintentionally contaminate foods such as milk,

grain, or fish during production or

harvesting, e.g., aflatoxins in

peanuts, polychlorinated biphenyls

(PCBS) in milk and fish, and mercury

in fish

Section 409

Section 402(a)(l)

Section 402(a)(l)

Section 706(b)(5)

cosmetics

for foods, drugs and

Section 409, subject to qualifications

of Monsanto v. Kennedy (described

in text)

Section 409, but DES proviso allows

this only if the amount of residue exceeds the detection limit set by FDA

Sections 408 and 409 (discussed under

FIFRA)

Section 402(a)(l) (covering substances

that would “ordinarily render [food]

injurious to health”)

Section 402(a)(l) [“May render injurious

to health”] or sections 402(a)(2)(a)

and 406 (which authorize the setting

of tolerances); FDA has tended to

set “action levels” which guide initiation of court action and seizure of

such substances under section

402(a)(l) (see ref. 127)

SOURCE: Office of Technology Assessment, 1987.

studies and clinical investigations to show that the drug

is safe and effective, a complete list of the drug composition, samples of the drug, information that may

be required for subsequent FDA monitoring activity,

and specimens of proposed labels (233), Any potential risks of inactive ingredients are also evaluated.

The agency shall not approve an application for a

new drug if it is not shown to be safe, if the available

information is not adequate to make that determination, or if the labeling is false or misleading. Otherwise, it “shall issue an order approving the application” (2 I U.S.C. 355(d)).

Some drugs are not in chronic or widespread use,

and have less potential for carcinogenicity. If a drug

is chronically used, FDA requires long term carcinogenicity studies in rodents (233). For oral contraceptives,

carcinogenicity tests in monkeys and dogs are required

as well (68). In addition, since the agency uses a riskbenefit balancing test to evaluate the safety of drugs,

“a drug . . . [that] has a significant effect on a fatal

disease with no alternative therapy could be regarded

as adequately safe despite major, even life threatening, side effects” (233). Thus, the agency would approve drugs taken chronically that have possible carcinogenic side effects only if “the benefits [were] judged

to exceed the risks (real and potential) under intended

conditions of use” (233).

Significant Judicial Decisions

One recent judicial decision is of note, for it may

influence developments in the future. In 1977, FDA

proposed an extreme procedure for regulating tiny

amounts of carcinogenic substances that may migrate

from packaging material into foods. The agency had

found that under certain laboratory conditions acrylonitrile monomers migrated from beverage containers

into the liquids contained inside, FDA argued that even

if improved manufacturing methods would decrease

the amount of acrylonitrile migrating into beverages,

packaging material with acrylonitrile in it could be presumed “to become a component of food, ” even though
206

present analytic methods could not detect it (237). The

agency argued that the burden is on the manufacturer

to prove that diffusion does not occur when packaging contains “lower residual levels of the material”

(237). The Court of Appeals for the District of Columbia in Monsanto v. Kennedy rejected this argument

(129). The Court was concerned

. . . that the Commissioner may have reached his determination [concerning small amounts of acrylonitrile in beverages] in the belief that he was constrained

to apply the strictly literal terms of the statute irrespective of the public health and safety considerations . . .

[but] there is latitude inherent in the statutory scheme

to avoid literal application of the statutory definition

of “food additive” in those de minimis situations that,

in the informed judgment of the Commissioner, clearly

present no public health or safety concerns (129).

In particular, the Commissioner

. . . has latitude . . . to find migration “insignificant”

even giving full weight to the public health and welfare concerns that must inform his decision . . . [and]

he would have latitude to consider whether acrylonitrile is generally recognized as safe at concentrations

below a certain threshold, even though he has determined for higher concentrations that . . . acrylonitrile

is not generally recognized as safe (129).

This case is important, not only because of its application to indirect food addtives, but because it introduces the idea of de minimis levels of risk into FDA

regulation and into the regulatory community more

generally. As discussed in chapter 3, it is generally believed that there are no “safe” threshold levels for carcinogens or that these levels have not been demonstrated, Under the Delaney clause, this belief would

seem to require that any concentration of a carcinogen as a food additive would have to be banned, for

there is no safe level. FDA, however, distinguishes legal arguments from scientific arguments and contends

that the Delaney clause is a policy statement and that

there are safe levels for carcinogens under the Delaney

clause. Since Monsanto v. Kennedy, some in FDA support the idea that there may be de minimis levels of

risk even with carcinogens.

A number of developments since Monsanto v. Kennedy indicate that FDA is adopting the idea of de

minimis risks for carcinogens. The agency permitted

lead acetate to remain in hair dye, even though it had

been found to be carcinogenic in animal feeding

studies, and even though some of it penetrated the

scalp and was detectable in the blood stream when the

dye was applied to hair (35). In addition, in 1982 the

agency approved D&C Green No. 6, “a color additive for use in drugs and cosmetics that was not itself

found to be carcinogenic, but contained a carcinogenic

constituent” (35), on grounds that Monsanto allowed

the agency some discretion in deciding how to deal

with color additives (39). A circuit court of appeals

has upheld such an approval since that time (35). In

1982 and 1983 FDA considered six color additives, all

of which had been found to be carcinogenic not merely

to have carcinogenic components. Rather than banning them outright, as the Delaney clause would seem

to require, the agency referred them to a panel of scientists at the U.S. Department of Health and Human

Services. “The clear, but unstated, implication of this

action is that the agency is now prepared to apply the

de minimis principle to direct food and color additives

that cause cancer in animals” (35). The agency may

also be trying to build a broad base of scientific support for its approach. In a related development on December 18, 1985, “FDA proposed to ban the use of

methylene chloride in cosmetics because it causes cancer in lab animals, but declined to lower the maximum

residue of it permitted in decaffeinated coffee because

that amount is considered safe” (35).

Monsanto v. Kennedy and subsequent developments contrast with an earlier case concerning the

FDA’s termination of provisional approval of Red No.

2 dye. In that instance, the agency had evidence that

Red No. 2 caused cancer in rats at low doses and

caused only a slight increase in cancer tumors (compared with those at low doses) at high doses. On this

basis, FDA proposed terminating provisional approval

of the dye and the industry sued. The court of appeals

upheld the agency’s action, (1) because the statistical

relationships in the initial animal studies, while not

providing “conclusive proof that Red No. 2 was a carcinogen, . . . [were] at least suggestive of it . . .“ and

(2) because these statistical relationships were later

confirmed at low doses. More important from the

Court’s point of view the study “could not be used to

establish safety . . .“ Thus the color’s safety was sufficiently questionable to justify FDA terminating its

provisional listing (27).

The Consumer Product

Safety Commission

Created in 1970 by the Consumer Product Safety

Act, the Consumer Product Safety Commission (CPSC)

is an independent regulatory agency headed by five

commissioners appointed by the President for staggered

seven-year terms. Its authority to regulate carcinogens

is established by both the Consumer Product Safety

Act (CPSA) and the Federal Hazardous Substances Act

(FHSA).

The Consumer Product Safety Act

CPSA gives the Commission power to regulate consumer products that pose “unreasonable risks” of in-
207

jury or illness (15 U.S.C. 2051) (1984). CPSC regulates all consumer products except foods and drugs,

pesticides, tobacco and tobacco products, motor vehicles, aircraft and aircraft equipment, and boats and

boat accessories (15 U.S.C. 2052(a)) (1984). The statute also precludes CPSC from regulating risks of injuries associated with substances that are, or are contained by, a consumer product “if such risk could be

eliminated or reduced to a sufficient extent by actions

taken under the Occupational Safety and Health Act

of 1970, the Atomic Energy Act of 1954, or the Clean

Air Act” (15 U.S. C. Sec. 2052(a)) (1984), and it may

not regulate “electronic product radiation emitted from

an electronic product” (15 U.S. C. 2080) (1984).

Whenever a product poses an “unreasonable risk”

of injury or illness, section 7(a) of CPSA authorizes

CPSC to promulgate a consumer product safety standard (15 U.S. C. 2056(a)(l)) (1984). The safety standard may specify requirements for product performance

or design, requirements for consumer instructions or

warnings, or both (15 U.S.C. 2056(a)(l)) (1984). If “no

feasible consumer product safety standard . . . would

adequately protect the public from the unreasonable

risk of injury” presented by a product, section 8 authorizes the Commission to ban the product from

commerce (15 U.S. C. 2052(a)(3)) (1984).

Mere risk of injury, death, or serious illness does

not by itself make a risk “unreasonable,” and the Commission has considered both risks and offsetting benefits in regulating products. Over time, the courts have

required that CPSC provide more extensive information to support its decisions concerning consumer

product hazards. Prior to 1978, while the Commission

indicated the benefits from a regulation in its regulatory rationales, it did not always provide a full description of the costs incurred by manufacturers and consumers because of regulation. In Aqua Slide ‘n’ Dive

v. the Consumer Product Safety Commission the

Court of Appeals for the Fifth Circuit invalidated a

requirement that warning signs be attached to home

swimming pools offered for sale. The court explained

“[t]he Commission does not have to conduct an elaborate cost-benefit analysis . . . It does, however, have

to shoulder the burden of examining the relevant factors and producing substantial evidence to support its

conclusion that they weigh in favor of the standard”

(10). Going on, the court said that “[t]he necessity for

the standard depends upon the nature of the risk, and

the reasonableness of the risk is a function of the burden a standard would impose on a user of the product. ” That burden can be measured by the “increases

in price, decreased availability of a product, and also

reductions in product usefulness . . . “ Moreover, the

Court suggested that CPSC had to show that consumers were unaware of the risks before a product regulation would be warranted (10).

Two other sections of the act might be used to regulate carcinogens (126). Section 12 permits the agency

to bring suit in Federal district court seeking the seizure of “an imminently hazardous consumer product”

or injunctive relief against a distributor (15 U.S. C.

2061(a)) (1976). This section apparently has not been

invoked against a product containing a carcinogen

(126). Section 15 authorizes the Commission to order

a variety of remedial actions with regard to any product that presents a “substantial product hazard, ” resulting from a product’s defect. (15 U.S. C. 2064) (1984).

The Commission intended to use this section to order

the recall of hairdryers containing asbestos and had

issued a preliminary conclusion that these hairdryers

presented a “substantial product hazard, ” but the manufacturers voluntarily recalled their hairdryers (126).

CPSA requires “informal rulemaking” to establish a

product safety standard or to ban a product (126).

In 1981 Congress amended CPSA by requiring that

CPSC convene a “Chronic Hazard Advisory Panel”

(CHAP) before issuing any proposed rule designed to

reduce exposures to a product presenting a risk of cancer, mutations, or adverse reproductive effects (15

U.S.C. 2081(b)(l)) (1984). Such a panel is appointed

by the Commission, consists of seven members from

a list of nominees submitted by the President of the

National Academy of Sciences. The nominees cannot

be Federal employees and must not have any “substantial financial interest in any manufacturer, distributor,

or retailer of a consumer product” (15 U.S. C. 2077(b)

(1)) (1984). The members must, in addition, be experts

capable of critically assessing “chronic hazards and

risks to human health” (15 U.S.C. 2077(b)(2)) (1984).

CPSC cannot take action until it receives a report from

such a panel. CPSC has convened CHAP’s since 1981.

The Federal Hazardous Substances Act

FHSA was enacted in 1960 as a labeling statute intended to fill gaps in other statutes. The act was later

amended to permit more drastic action to control hazards and expanded “to cover hazardous substances in

general use in the home, and particularly to protect

children from hazardous toys and products” (Poison

Prevention Packaging Act of 1970, Public Law 91-601,

84 Stat. 1670 (1970); Child Protection and Toy Safety

Act of 1969, Public Law 91-113, 83 Stat. 187 (1969);

ChiLd protection Act of 1966, Public Law 89-756, 8

Stat. 1303 (1966)) (126). FHSA was administered by

the Food and Drug Administration until the creation

of CPSC, at which time the new agency took responsibility for the act.
208

Section 2(f)(l)(a) of FHSA defines “hazardous substance” as a substance or mixture which “. . . may

cause substantial personal injury or substantial illness

. . . as a proximate result of any customary or reasonably foreseeable handling or use, including reasonably foreseeable ingestion by children” (15 U.S.C. Sec.

1261(f)(l)(a)) (1984). The act excludes, among other

things, pesticides, foods, drugs and cosmetics, certain

radioactive materials, and tobacco and tobacco products. Under FHSA, CPSC may require a hazardous

substance to bear a hazard label or, if CPSC determines that this step would be insufficient, to ban the

product from commerce. CPSC has authority to seize

banned substances and to require businesses to repurchase banned hazardous substances (15 U.S. C. 1264)

(1984).

In contrast to CPSA, FHSA has slower and more

complex rulemaking requirements. The agency issues

a proposed rule, entertains comments, and publishes

a “final order” (126). If parties adversely affected by

the order file “legally sufficient” objections, the Commission is obligated to conduct an evidentiary hearing before an administrative law judge (126). In effect,

this procedure is much like formal rulemaking on top

of informal rulemaking. Any party whose products

have been banned as hazardous under FHSA may petition a court of appeals within 60 days for review

(126). A reviewing court must affirm the Commission’s

order if the order is “based on a fair evaluation of the

hearing record” (126).

The Commission has preferred to rely on CPSA because of FHSA’S more complex rulemaking and because it believes the informal procedures of the CPSA

would better facilitate participation by diverse interests (229). This preference has recently been overruled

for some kinds of cases, however. In the recent formaldehyde decision heard by the 5th Circuit Court of

Appeals, the court noted that “[r]ulemaking under the

Consumer Product Safety Act is to be the exception,

not the rule . . . “(76).

Major Court Decisions

Four major legal decisions have affected CPSC regulation of carcinogens. Three cases concerned procedural matters: Pactra Industries v. CPSC (153),

Springs Mills v. CPSC (190), and Dow Chemical v.

CPSC (45). The major lesson from the cases is that the

Commission must scrupulously follow due process requirements in issuing regulations (110).

In Dow Chemical v. CPSC, the Commission attempted to use its cancer policy, which had been issued as part of a proposed rulemaking, to classify substances according to evidence of their carcinogenicity.

Using the policy, the Commission provisionally classified perchloroethylene as a suspect carcinogen. The

Dow Chemical Company sued because it believed even

such a provisional classification harmed Dow. The

court held that CPSC could not rely on the cancer policy in this manner until it was adopted in rulemaking

procedures (45). Subsequent to this decision CPSC formally withdrew its cancer policy from the rulemaking process and decided to use the guidelines adopted

by the Interagency Regulatory Liaison Group (IRLG),

and more recently the guidelines issued by the President’s Office of Science and Technology Policy (OSTP).

(Both are discussed more fully in ch. 2.) CPSC had

intended to issue a legally binding cancer policy, hoping to foreclose some legal debates in issuing carcinogen regulations. The Dow Chemical court blocked the

attempt. At present the Commission’s position is that

it may refer to guidelines such as the old IRLG or

present OSTP cancer guidelines, but cannot use them

to foreclose legal debates until they have been formally

adopted as legal documents in rulemaking procedures.

In addition, there are some legal issues that cannot be

foreclosed by publishing a cancer policy, e.g., whether

a particular animal bioassay is a valid scientific experiment or not.

A fourth case concerning CPSC’s regulation of carcinogens could have more far-reaching impact. In

1982, after a 6-year investigation and rulemaking regarding urea-formaldehyde foam insulation (UFFI), the

Commission issued a final rule banning UFFI in residences and schools (76). Four industry petitioners objected to the ban and convinced the 5th Circuit in Gulf

South Insulation v. Consumer Product Safety Commission to overturn the ban on UFFI (76). In particular, the court objected to the Commission’s “exclusive

reliance” on a single animal study to support its risk

assessment (76). About a large animal bioassay involving 300 animals, the court noted that

. . . in a study as small as this one, the margin of error is inherently large. For example, had 20 fewer rats

or 20 more developed carcinomas, the risk predicted

by [the] Global 79 [risk assessment model] would be

altered drastically (76).

This is very close to saying that if the victim of the

gunshot wound had not died, the defendant wouldn’t

be guilty of murder.

The court went onto conclude that even if the study

were valid for some purposes, it did not constitute substantial evidence to support CPSC’s “precise” estimate

of risk, without which CPSC could not validly conclude that UFFI posed an unreasonable risk of cancer.

The court believed that formaldehyde “should be

presumed to pose a cancer risk to man, ” but regarded

as “questionable” two assumptions the Commission

relied upon: that at identical exposure levels the “effective dose for rats is the same as that for humans,”
209

and that the “risk of cancer from formaldehyde is linear at low dose—in other words that there is no threshold below which formaldehyde poses no risk of cancer” (76). Finally, as indicated above, the court held

that CPSC had not properly justified its rulemaking

under CPSA rather than FHSA, concluding that the

Commission should have regulated UFFI under the

Federal Hazardous Substances Act (76).

The Environmental Protection Agency

In 1970 by executive order, President Richard Nixon

created the Environmental Protection Agency, merging 15 existing programs “managed by 5 different departments or councils . , . into . . . an organization

headed by a single administrator . . . charged with regulating virtually all sources of pollution rather than

a single industry” (114).

EPA is headed by an administrator, with assistant

administrators in charge of its major divisions. (Table

A-3 lists EPA units responsible for administrating the

various environmental statutes. )

The Clean Air Act

One of the first major environmental statutes

enacted in the early 1970s was the Clean Air Act

Amendments of 1970. The statute provides an

elaborate Federal-State scheme for controlling conventional pollutants, such as sulfur dioxide and carbon

monoxide. Because of the emphasis on controlling conventional air pollutants, toxic pollutants were almost

ignored. The House version of the bill did not contain a provision for hazardous air pollutants (although

the Senate version did) and during the House-Senate

Conference negotiations, the administration recommended deletion of the hazardous pollutants section

(71). Despite this opposition, Congress approved a

hazardous air pollution provision–section 112.

While sections 108-109 and 111 have been considered by EPA as possible statutory authority for regulating carcinogens, the agency has not relied on these

and has used section 112 as its primary authority.

However, in 1977 Congress amended CAA by adding, among other things, a section on the regulation

of radioactive pollutants, cadmium, arsenic, and polycylic organic matter. The agency was ordered to review within one year all “available relevant information” on these substances to decide whether or not they

“may reasonably be anticipated to endanger public

health” (42 U.S, C. 7422(a)). If any did, it was to be

considered for regulation under sections 108-109, 111

or 112, or a combination of them. The agency subsequently regulated two of these substances. (See ch. 4.)

Section 112 authorizes EPA to set emission standTable A-3.—EPA Administration of Statutes

EPA office Statute administered

Assistant Administrator for

Air and Radiation

Assistant Administrator for

Pesticides and Toxic

Substances

Office of Pesticide

Programs

Office of Toxic Substances

Assistant Administrator

Solid Waste and

Emergency Response

Assistant Administrator

for Water

for

Clean Air Act

Federal Insecticide,

Fungicide, and

Rodenticide Act

Toxic Substances Control

Act

Resource Conservation

and Recovery Act,

Comprehensive

Environmental Response,

Compensation, and

Liability Act (Superfund)

Clean Water Act, Safe

Drinking Water Act

-

SOURCE: Office of Technology Assessment, 1987.

ards for “hazardous” air pollutants, which include any

air pollutant

. . . to which no ambient air quality standard is applicable and which in the judgment of the Administrator causes or contributes to, air pollution which may

reasonably be anticipated to result in an increase in

mortality or an increase in serious irreversible, or incapaciting reversible, illness (42 U.S. C. 7412(a)(2)).

The administrator must establish standards for each

pollutant

. . . which in his judgment provides an ample margin of safety to protect the public health from such

hazardous air pollutant. (42 U.S.C. 7412(b)(l)(b)).

Under this section EPA was required within 90 days

of December 31, 1970, to publish, and from time to

time revise, a list of hazardous air pollutants that EPA

intends to regulate (42 U.S.C. 7412(b)(l)(a)). The idea

is that a pollutant is first listed as hazardous based on

pertinent scientific data, then national standards are

established for each source category of such pollutants

(71).

A substance can become a candidate for listing by

agency nomination or by citizen petition (71). A substance is not listed until the EPA staff prepares a comprehensive health assessment document, the agency’s

Scientific Advisory Board (SAB) gives written comment, and the EPA administrator determines to list it

(71).

Once a substance is listed, the administrator is to

propose emission standards within 180 days, hold a

public hearing within 30 more days, and publish final

emission rules within 180 days of the proposal (42

U.S.C. 7412(b)(l)(b)). The pollutant must be regulated
210

“unless [the agency] finds, on the basis of information

presented at such hearings, that such pollutant clearly

is not a hazardous air pollutant” (42 U.S.C. 7412(b)

(l)(b) )(1982). Once a substance is listed as a hazardous pollutant, the administrator has a duty within the

deadlines to propose and issue national emission standards, and citizens may sue in Federal courts to force

compliance with these procedures (42 U.S. C. 7604

(a)(2)).

States may issue their own standards for hazardous

air pollutants “as long as they are at least as stringent

as those required by EPA. If States submit adequate

control programs to EPA, the administrator is authorized to delegate his implementation and enforcement

authority to the States” (76).

However, Congress provided no explicit guidance

for regulating carcinogens as compared with other hazardous substances under this section. This failure to

address carcinogens explicitly has led to considerable

controversy in the interpretation of the statute for application to carcinogens. For a substance with a toxic

threshold, i.e., a level below which there are no harmful health effects to a group of people, setting a standard would involve determining a “no effects” threshold and providing for a margin of safety. However,

for carcinogens there is no known safe threshold.

Thus, providing an ample margin of safety as required

by the statute would imply elimination of all exposures

by setting an emissions standard of zero, or, possibly,

a standard of no detectable concentrations. Faced with

economically beneficial activities which produce such

pollutants and with control equipment incapable of reducing emissions to zero, EPA’s strategy has been to

require

. . . emission reduction to the lowest level achievable by use of the best available control technology in

cases involving apparent nonthreshold pollutants,

[where] complete emission prohibition would result

in widespread industry closure and EPA has determined that the cost of such closure would be grossly

disproportionate to the benefits of removing the risk

that would remain after imposition of the best available control technology (325),

The definition of “best available technology” (BAT)

differs for new and existing sources. For existing

sources EPA considers “economic feasibility” and sets

the requirements at “the most advanced level of technology that at least most members of an industry [can]

afford without plant closures” (325). For new sources,

BAT will be the “technology which in the judgment

of the administrator, is the most advanced level of control adequately demonstrated, considering economic,

energy, and environmental impacts” (324). In addition

to requiring BAT, for new sources, if EPA finds that

there is an “unreasonable residual risk, a more stringent alternative would be required” (324). The administrator will base his judgment of “unreasonable residrisk” on:

the range of additional cancer incidence;

the range of health risks to the most exposed individuals;

readily identifiable benefits of the substance or the

activity;

economic impacts of requiring additional control

measures;

the distributions of benefits of the activity versus

the risks it causes; and

other possible health and environmental risks

(324).

Although this overall strategy was articulated in a proposed rule adopting a policy for airborne carcinogens

(324) which has never been finalized by the agency,

EPA staff say that the agency continues to follow the

broad outlines of the policy (103). EPA has acknowledged that the BAT approach was not explicitly recognized by the statute and, at the time it regulated asbestos and vinyl chloride, the approach had not been

tested in the courts.

The court test arose over the 1976 vinyl chloride

standards (55). That case ended with a consent decree

in which EPA agreed to issue proposed amendments

to the standard for vinyl chloride with “the ultimate

goal of zero vinyl chloride emissions.” In addition,

EPA agreed to lower the 10 ppm emission standard

to 5 ppm as soon as “technology can achieve the lower

standard” as a means of working toward the zero emission standard (55), EPA’s interpretation of the “ample margin of safety” requirement of section 112 has

been controversial. The General Accounting Office as

well as others have disagreed with the agency’s position (183,198). Nevertheless, it received tacit endorsement by the courts when the District of Columbia

Court of Appeals approved the consent decree.

Subsequent to the consent decree in EDF v. Train,

there has been further litigation concerning regulation

of vinyl chloride and EPA’s interpretation of “ample

margin of safety. ” On January 9, 1985, EPA announced that it would not continue to pursue the goal

of zero emissions for vinyl chloride and would not require a standard of 5 ppm (compared with the present

10 ppm). It supported its position on several grounds:

●

●

●

EPA continues to hold that section 112 does not

“express an intent to eliminate totally all risks

from emissions of airborne carcinogens” (325),

10 ppm represents “the lowest level of control

which has been consistently achieved” (325), and

the proposed 5 ppm emission “was not based on

data from a control technology different from that

analyzed for the current standard” (325).
211

The Natural Resources Defense Council (NRDC), alleging that EPA had “reneged” on provisions of the

1977 consent decree, sued EPA on June 17, 1985, concerning its interpretation and procedure for setting

standards under the “ample margin of safety” phrase

(142). NRDC argued that the language of the statute

does not specifically provide for cost-benefit analysis,

and, additionally, section 112 does not permit EPA to

impose cost-benefit or technological feasibility tests on

proposed standards for toxic pollutants. NRDC argues

that the Supreme Court has held that the agency cannot use cost-benefit analysis when setting health standards unless the statute provides for it (140). A panel

of the D.C. Circuit ruled in 1986 that, since the statute provides EPA with some discretion in setting regulations under section 112 and since it does not specify

precisely how this discretion is to be exercised, the

court will permit the agency to exercise reasonable discretion in implementing the statute. However, the

panel decision was subsequently vacated by a grant

of rehearing for certain source categories by the entire court. Oral argument was held on April 29, 1987,

and a decision is pending.

In addition, the Agency has been sued over its failure to issue benzene standards. NRDC argues that the

statute requires that hazardous air pollutant regulations be based exclusively on public health considerations, not technology and cost tests which may compromise the protection of health. It also argues that

EPA is prohibited by statute from dismissing as insignificant an increase in mortality that may be caused

by benzene exposure, because the agency is required

to issue regulations with an ample margin of safety,

not simply to prevent “significant” health risks (145).

The agency responds that section 112 of the Clean

Air Act permits “EPA not to regulate source categories of benzene that present an insignificant risk” (146).

The contention is that Congress, in its 1977 amendments, “intended to codify an approach . . . [taken in

an earlier legal case] . . . which plainly held that a

finding of ‘significant risk’ is an appropriate test for

regulating and stressed that the administrator may

‘weigh risks and make reasonable projections of future trends’ . . . “ (146).

The outcome of this case will be important for the

development of hazardous air pollutant regulations,

and it may also indicate the extent to which the courts

are willing to permit agencies not to regulate toxic substances because the agency has determined that the risk

is “insignificant” or “de minimus. ”

The Clean Water Act

Since the Federal Water Pollution Control Act was

first enacted in 1948, it has been amended nine times,

and is now generally referred to as the Clean Water

Act. The most important of the amendments were

made in 1972, 1977, and 1987. In 1972, Congress set

the goal of achieving “fishable, swimmable” waters by

1983 and prohibiting the “discharge of toxic pollutants

in toxic amounts . . .“ by 1985 (33 U.S.C. 1251(a))

(1982). In the 1977 amendments, Congress endorsed

a new method for regulating toxic pollutants that had

been developed to settle a lawsuit between environmental organizations and EPA. In 1987, Congress

continued its emphasis on control of toxic pollutants.

The CWA protections are less directly related to

human health than are the protections of some other

laws such as the Safe Drinking Water Act, which aims

at securing the safety of drinking water supplies.

Nonetheless, CWA has a number of sections aimed at

regulating human exposure to carcinogens and other

toxics.

Central to controlling all water pollutants under

CWA are the National Pollution Discharge Elimination System (NPDES) permits for “direct” dischargers.

It is lawful to discharge a pollutant only if the discharge

is in compliance with an NPDES permit. Such permits

can be issued by EPA or by States whose permit programs are approved by EPA. At present 37 of a possible 54 jurisdictions have been approved to administer their own NPDES programs; EPA administers the

remainder (31).

An NPDES permit is written for a facility which may

have a number of discharge pipes (typical facilities

have from 1 to 3 such pipes, but large facilities like

steel mills may have as many as 100) (74). For each

discharge pipe a permit will contain the following:

a list of pollutants that must be regulated according to Federal or State law, together with specified permissible amounts of each pollutant that

may be discharged per unit of time;

monitoring requirements and schedules for implementing the pollution concentration requirements; and

special conditions regarding pollutants the permit

writer thinks should be imposed on the permit

holder, for example, additional testing and procedures for spills of pollutants into the water.

NPDES permits are written both for conventional pollutants (e.g. biological waste material) and for toxic

substances.

In writing a permit for toxic substances such as carcinogens, the responsible State agency or EPA will consider the folIowing:

• Federal toxic effluent standards and toxic effluent

limitations,

• Federal water quality criteria for toxics,

● State water quality standards or effluent stand-
212

ards for toxics, and

• special conditions.

Sections 301, 304, and 307 of CWA are the centerpiece, containing substantive conditions on NPDES

permits for regulating toxic pollutants. Under it, EPA

may issue binding regulations known as effluent limitations and effluent standards. These are legally binding Federal regulations limiting the concentrations of

pollutants in point source discharges and they must

be on NPDES permits.

An “effluent limitation” uses a technology-based approach to limit the amount of a toxic substance that

can be discharged from a point source, such as a pipe.

Toxic substances regulated in this manner have been

regulated on an industry by industry basis. z An “effluent based standard, ” by contrast, is a control requirement based on the relationship between the discharge of a pollutant and the resulting water quality

in a receiving body of water (62), but has not been

used since 1977. Water quality-based effluent limitations which specify certain concentrations of a chemical in a point source of effluent, are typically more

stringent than technology-based effluent limitations

(62), and must be established “with an ample margin

of safety” (33 U.S.C. 1317(a)(4)) (1982). Finally, CWA

requires informal rulemaking (79).

Because only six pollutants had been regulated with

effluent standards, EPA was sued by NRDC. The subsequent consent decree (discussed below) provided that

EPA could instead set effluent limitations to regulate

toxic pollutants. In 1977, Congress added a reference

to a specific list of toxic substances that had been

agreed to for the consent decree. (See table 1 of the

House committee on Public Works and Transportation Committee Print 95-30. ) An account of how this

list of toxic pollutants was developed is provided in

chapter 3. This list may be revised from time to time

as the administrator deems appropriate (loll;

1317(a)) (1982).

For each listed toxic chemical the administrator must

establish effluent limitations or standards. Substances

controlled by either of these mechanisms have been

regulated on a pollutant-by-pollutant basis. Effluent

limitations are issued industry-by-industry, however,

with specific requirements for each relevant pollutant.

Effluent standards, when used, have been issued pollutant-by-pollutant, regardless of which industries

might be affected.

‘Best availabIe technology provisions for regulating toxic substances were

not included in the major revisions of CWA in 1972. Section 307 originally

included only the nontechnology-based toxic effluent standards. Congress

amended CWA in 1977 to provide for technology-based limitations as agreed

to in the 1976 NRDC v. Train consent decree.

Section 307(b) also requires pretreatment standards

for toxic substances discharged from private pollution

sources into publicly owned water treatment facilities.

Pretreatment standards together with discharge limitations on publicly owned treatment facilities must

produce as great a reduction of toxic pollutants as the

use of effluent limitations would on a private polluting point source (33 U.S. C. 1317(b)).

Section 306 requires technology regulations on new

facilities similar to effluent limitations on existing facilities (so-called new performance standards). New facilities must provide the best available demonstrated

technology and, where it is practicable, there must be

no discharge of pollutants (33 U.S.C. 1316).

Section 304 authorizes EPA to develop ambient

water quality criteria for all pollutants, including

toxics. These criteria are not legally binding on EPA

or the States, but may be used as pollutant goals to

be pursued in improving the quality of water courses.

The production of the water quality criteria documents

was a major risk assessment activity at EPA in the late

1970s (see ch. 4). NPDES permit writers, under the

narrative criteria of the permits, may impose more

stringent limitations on toxic pollutants than BAT effluent limitations would require. The extent to which

permit writers have used this section of NPDES permits is unknown, but some in EPA believe that EPA

regional offices do use the ambient water quality criteria in writing permits for facilities in States where

there are not State-approved programs (15).

State water quality standards are to be developed

for the amount of a pollutant permitted in a given

course (sec. 303). The limitations established here must

protect the public health or welfare, enhance the quality of water, and serve the purposes of the act. CWA

requires that the States develop State water quality

standards. The extent of this standards-setting activity, however, has been very limited (see ch. 3).

Water quality-based effluent limitations, adopted

under section 302, might be used to impose “limitations more stringent than BAT for sources on a particular stream segment, ” such as the prohibiting of all

discharges of toxic pollutants, “if the water quality in

a stream will not attain the national goal of “fishable/

swimmable’ waters . . .“ (62). To date this section has

not been used, but EPA has announced its intention

to begin to develop such standards (282). However,

the agency will first develop limitations for fish and

aquatic life and acknowledges that the human health

limitations “lag behind” (15).

Special conditions imposed by an NPDES permit

writer are designed to achieve a generalized goal, or

narrative criteria, of the State water laws or CWA,

e.g., preventing toxic pollutants in toxic amounts in

the nation’s waters (sec. 301).
213

In addition to regulating toxic substances, CWA

declares that there should be no discharges of “oil or

hazardous substances” into or on the navigable waters,

including shoreline coastal waters. Hazardous substances are those that present an “imminent and substantial danger to the public health or welfare . . .“

(33 U.S.C. 1321(b)(2)(a)). EPA was required to list

such substances, determine quantities which might be

harmful, and issue regulations concerning these (33

U.S. C. 1321(b)(2)(a), 1321(b)(4)). The law also provides for liability in case of discharges of hazardous

substances or oil. This provision of CWA anticipates

some of the hazardous substances prevention and

cleanup provisions of the later Resource Conservation

and Recovery Act and the Comprehensive Environmental Response, Compensation, and Liability Act.

Significant Judicial Decisions.—A judicial decision

led to the development of toxic effluent limitations under CWA. In 1975a group of lawsuits were filed against

EPA challenging its failure to regulate toxic pollutants

(55). In 1976 those cases ended in a consent decree,

with EPA agreeing to place specific “numerical limits

on the quantities of 65 toxic pollutants in 21 industrial categories” (62). EPA was required to complete

these regulations by June 30, 1983. The consent decree

permitted EPA to regulate toxic substances through

those sections of CWA designed to control ordinary

nontoxic pollutants, in particular, the technologybased provisions of the statute. The agency has been

in the process of issuing BAT effluent limitations for

28 industrial categories which may limit these 65 categories of toxics, including at least 29 carcinogens.

Congress, in the 1977 amendments to the CWA, incorporated these changes, in effect creating the new

category of toxic effluent limitations.

There have been several judicial developments related to the 1976 consent decree. The National Research and Demonstration Center sued EPA to show

the agency in contempt of the agreement (this was settled out of court, extending EPA’s original deadline

from June 30, 1983, to June 30, 1984) (140). Eight times

EPA requested Judge Flannery to modify the agreement to give it more time to complete the regulations.

Except for the May 1982 request, which Judge Flannery denied, urging the agency to “work harder, ” (144)

the requests were granted (144). These guidelines are

in various stages of revision and litigation.

Another judicial development of note was Velsicol

Corporation’s attempt to overturn EPA’s first regulations of two toxic substances, toxaphene and endrin,

regulated under the Federal Water Pollution Control

Act of 1972. Velsicol argued, among other things, that

the technology-based effluent limitations added in the

1977 congressional amendments superseded the previous health-based authority of section 307 and that,

in addition, EPA was required to consider economic

and technological factors in setting its regulations. The

court ruled that the 1977 amendments were required

to aid, not impede, EPA’s health-based authority, and

thus denied both pleas (and several others as well) (88).

One final judicial development of note is EPA’s use

of “fundamentally different factors” (FDF) variances.

These have been used to modify, on a case-by-case basis, BAT or pretreatment limitations of pollutants, including toxics (62). However, such variances are not

specifically authorized by the statute and have been

the subject of some litigation. Although the Court of

Appeals for the Third Circuit struck down the use of

these variances, the Supreme Court in a 5-4 opinion

upheld EPA’a authority to apply FDF variances to

toxic pollutants (29).

The Safe Drinking Water Act

A second major statute for regulating carcinogens

in water is the Safe Drinking Water Act (SDWA) of

1974. Although the Clean Water Act, discussed above,

was designed to control water pollution, it Provided .

no authority to regulate polluted water discharged into

nonnavigable waters, such as groundwater, which

often is a source of drinking water. Thus additional

legislation was needed to “assure safe drinking water”

(214). SDWA aims primarily to regulate water provided by public water systems, and it contains several provisions that may be used to regulate hazard- —

ous substances, including carcinogens in drinking

water. In contrast to CWA, SDWA is more directly

concerned with protecting human health.

Under SDWA, EPA is to regulate contaminants

“which . . . may have an adverse effect on the health

of persons . . .“ (42 U.S.C. 300f(l)(b)). The act then

prescribes the steps which the agency must go through

over time to protect drinking water.

First, EPA was required to publish national interim

primary drinking water regulations within 90 days of

December 16, 1974. These regulations were to “protect health to the extent feasible, using technology,

treatment techniques and other means, which the Administrator determines are generally available (taking

costs into consideration)” on the date of enactment (42

U.S.C. 300g-l(a)(2)).

Second, Congress required that EPA request a National Academy of Sciences (NAS) study to determine

the maximum contaminant levels that should be recommended as national standards, and to identify the

“existence of any contaminants the levels of which in

drinking water cannot be determined but which may

have an adverse effect on the health of persons” (42

U.S.C. 300g-2(e)). In addition, revisions of the NAS

study reflecting any new information “shall be reported
214

to Congress each two years thereafter” (42 U.S.C.

300g-2(d)(2)).” In considering whether contaminants

have an adverse effect, the NAS study had to consider

the impact of contaminants on groups or individuals

in the population more susceptible to adverse effects

than normal healthy individuals, as well as exposure

to contaminants in other media, synergistic effects of

contaminants, and body burdens of contaminants in

exposed persons (42 U.S.C. 300g-1(3)). In 1977 NAS

provided its first list of contaminants (chosen on the

basis of its own criteria) that might have an adverse

effect on health (36,134).

Third, within 90 days of the publication of the NAS

study, EPA was required to establish by rulemaking

“recommended maximum contaminant levels (RMCL)

for each contaminant which . . . may have any adverse effect on the health of persons” (42 U.S.C. 300gl(b)(l)(b). Each such RMCL was to be “set at a level

at which . . . no known or anticipated adverse effects

on the health of persons occur and which allows an

adequate margin of safety” (42 U.S.C. Sec. 300g-l(b)

(1)(b)).

The House report on the 1974 SDWA elaborated on

the criteria for setting RMCLS:

. . . the recommended maximum level must be set to

prevent the occurrence of any known or anticipated

adverse effect, It must include an adequate margin of

safety, unless there is no safe threshold for a contaminant. In such a case, the recommended maximum contaminant level should be set at zero level (214).

RMCLS are nonenforceable health goals, which are

used as guidelines for establishing enforceable drinking water standards. The agency also had to publish

a list of contaminants whose levels cannot be measured accurately enough in drinking water to establish

an RMCL, and which may have an adverse effect on

the health of persons (42 U.S.C. 300g-l(b) (1)(b)).

Once the agency established RMCLS for each contaminant it was required to publish revised national

primary drinking water regulations. These regulations

establish the requisite enforceable health standards.

The required regulations must specify a maximum contaminant level (MCL) or require the “use of treatment

techniques for each contaminant” for which an RMCL

is established. The established MCLS were to be as

close to the RMCLS as is “feasible” (42 U.S. C. 300gl(b)(3)), In determining feasibility, the administrator

may consider “the use of the best technology, treatment techniques and other means, . . . [that] are generally available (taking cost into consideration)” (42

U.S.C. 3oog-l(b)(3)).

In general, enforcement of MCLS rests with the

States. EPA sets MCLS. The agency then has the

responsibility of reviewing and approving State programs to achieve the mandated standards, and, once

a State program is approved, it gives States the authority to enforce the MCLS. Until a State has an approved program, EPA has authority to regulate levels

of contaminants in drinking water.

SDWA was modified by the 1986 Amendments

which are discussed in chapter 3.

Significant Judicial Action.—To date only one case

has been brought regarding EPA’s regulation of carcinogens (concerning the regulation of trihalomethanes)

under SDWA, and it was settled after briefs were filed.

Since the agency issued a final rule for RMCLS and

a proposed rule for MCLS for eight volatile organic

compounds in November 1985, it has been sued by

both industry and environmental organizations. Environmental organizations are challenging the classification of 1,1-dichloroethylene as category II in EPA’s

weight-of-the-evidence classification scheme and contend that that there should be zero concentration levels

for RMCLS for carcinogens regardless of the weight

of the evidence.

The Federal Insecticide, Fungicide,

and Rodenticide Act

The Federal Insecticide, Fungicide, and Rodenticide

Act was originally passed by Congress in 1947. This

act was replaced by the Federal Environmental Pesticide Control Act (FEPCA) of 1972, although the name

FIFRA continues to be used. Central to regulating the

sale, shipment, and delivery of pesticides is a registration system: generally, it is unlawful to sell or distribute a pesticide which is not registered with EPA

(7 U.S.C. 136j(a)(l)(a)).

Registration of New Pesticides.—An applicant for

registration of a pesticide must file certain required information, including a statement of all claims made

for the pesticide, directions for its use, a description

of tests made upon it, and the test results used to support claims made for the substance with EPA (7 U.S.C.

136a(c) (l)(a-d)). Most important for this report is that

an applicant must supply appropriate health and safety

data for each pesticide.

In a typical registration procedure a prospective

registrant, typically the pesticide manufacturer, submits an application for a registration. If a registration

package contains all required material it goes on for

an evaluation of toxicity studies, wildlife data, exposure information, etc. At the same time, if appropriate, the agency considers residue data for purposes

of setting food-safety tolerances as required under sections 408 and 409 of FDCA (described below).

FIFRA requires that EPA “shall register” a pesticide

if its composition warrants the proposed claims for it,

and its labeling and other required material comply

with the requirements of the Act (meaning “it will per-
215

form its intended function without unreasonable adverse effects on the environment, ” and “when used in

accordance with widespread and commonly recognized practice it will not generally cause unreasonable adverse effects on the environment” (7 U.S.C.

136a(c)(5))). “Unreasonable adverse effects on the environment” means “any unreasonable risk to man or the

environment, taking into account the economic, social and environmental costs and benefits of the use

of any pesticide” (7 U. S. C.136(bb)). The agency may

refuse to register a pesticide after giving the applicant

notification of this intention and opportunity to correct the deficiencies in the application (7 U.S. C.

136a(c)(6)).

If EPA finds that a pesticide meets or exceeds any

of several criteria for risk specified by EPA which includes carcinogenicity (40 CFR 154.7), it must initiate

the special review process. During the special review,

the risks and benefits of the pesticide are considered

and public comments received. Unless the manufacturer can show EPA is wrong, or that exposures would

not be significant, proceedings are initiated to deny,

cancel, or modify the registration of the pesticide.

A pesticide may be registered for general use or restricted use. If a chemical will not “generally cause unreasonable adverse effects on the environment, [EPA]

will classify” it for general use (7 U.S.C. 136a(d)(l)(b)).

If it “may generally cause, without additional regulatory restrictions, unreasonable adverse effects on the

environment, including injuries to the applicator,

[EPA] shall classify” it for restricted use (7 U.S.C.

136a(d) (1)(c)). Nearly all pesticides are registered for

particular uses, such as for particular crops (328). If

a registrant desires to sell a product for a use not permitted by the registration, then he or she must submit

it for agency approval and registration for that different use. If the agency classifies a pesticide for restricted

use because “the acute dermal or inhalation toxicity

of the pesticide presents a hazard to the applicator or

other persons, ” then it shall be applied only by or under the direct supervision of a certified applicator (7

U.S.C. 136a(d)(l)(c)(i)). The States have the authority to certify pesticide applicators (7 U.S.C. 136b(a)

(2)).

In registering a pesticide for use, EPA’s approval requires the granting of a residue tolerance if pesticide

residues are expected to remain on a raw foodstuff,

or to issue an exemption from the tolerance requirement if appropriate. The setting of a tolerance is required by section 408 of the Food, Drug, and Cosmetic

Act. Sections 408 and 402(a)(2)(b) of FDCA forbid the

distribution of raw or processed foods bearing pesticide residues that have not been sanctioned by EPA

(21 U.S.C. 342(a)(2), 346a(a)). Unlike the Delaney

clause of section 409 of FDCA (concerning food additives), residues of pesticides used on foodstuffs are not

precluded even when they induce cancer in laboratory

animals (127). However, EPA must determine the

quantity of a pesticide that may remain on a raw commodity when it enters commerce and must set an

appropriate tolerance for the substance (21 U.S. C.

346a(a)). In setting a tolerance, the agency must take

into account the necessity for an “adequate, wholesome, and economical food supply, ” other ways consumers may be affected by the same or other chemicals, and the opinion of the Secretary of Agriculture,

“submitted with a certification of the usefulness” of

the pesticide (21 U.S.C. 346a(a)).

EPA also must set tolerances for pesticide residues

in processed agricultural products, such as grain flours

or processed vegetable or fruit products, under section 409 of the Food, Drug, and Cosmetic Act. A pesticide residue becomes a “food additive” and thus may

be subject to the Delaney clause, if the processing increases the residue concentration levels in the processed

food above the tolerance established for the raw commodity (21 U.S. C. 342(a)(2)(c)). If the concentration

after processing remains below that established for the

raw commodity, the Delaney clause does not apply

(127). EPA sets the pesticide residue limits, and FDA

monitors and enforces the regulations.

When Congress amended FIFRA in 1978, it permitted “conditional registration” of a pesticide, even

though some of the test data may not have been submitted to or evaluated by EPA. The Agency may conditionally register pesticides if “insufficient time has

elapsed since the imposition of the data requirements

for those data to have been developed, use of the pesticide product(s) containing the new active ingredient

during the conditional period would not cause any unreasonable adverse effects, and conditional registration of the pesticide product and its uses are in the public interest” (203). Even though Congress intended

conditional registrations to be “rarely exercised, ” EPA

conditionally registered about half the pesticides submitted between 1978 and 1984 (203).

Pesticides contain both “active” and “inert” ingredients. Active ingredients are the components in pesticides that prevent, destroy, repel, or mitigate any

pest, or disrupt the normal biological functioning of

certain organisms such as insects, fungi, and plants (21

U.S.C. 136(a) (l-4)). An inert ingredient is one that is

not active in this sense. Typically inert ingredients are

used to dilute or deliver the active ingredients.

In the past most regulatory attention in registration

has been focused on active ingredients, for they are

typically the ones that damage pests or plants. However, there has been increasing concern about inert ingredients because they may have dangerous health effects (2). Problems with inert ingredients are described
216

in chapter 3. EPA issued a policy statement for regulating inert ingredients on April 22, 1987 (295). EPA

intends to encourage the use of the least toxic inert ingredients, require data to determine the conditions of

safe use of particular inerts, require labeling, and hold

hearings to determine if the use of certain inerts should

continue.

Special Reviews, Cancellation, Suspension of Registered Pesticides.—In addition to the cancellation provisions of FIFRA, section 6, once a substance has been

registered, if data indicate that it may present an acute

toxicity or a chronic toxicity hazard, including oncogenicity, or if it lacks an emergency procedure in case

of exposure, EPA may announce a “special review”

(40 CFR 154.11 (a)(3)). Until 1983 these had been

known as “rebuttable presumptions against registration (RPAR)” (2). Unless the data on which the special review is based are shown to be unreliable or invalid, or the estimated benefits of continued uses

(possibly with additional restriction) outweigh the estimated risks, the pesticides are candidates for cancellation or suspension of their registration (360).

Reregistration of Pesticides Registered Prior to 1972.–

When FIFRA was amended in 1972, a number of pesticides were in use that had neither been registered under the new statute nor subjected to more stringent

data requirements. Congress required a review of all

substances then registered, to reassess the safety of

those pesticides. The “reregistration” was intially to

be completed by 1976, but in 1975 Congress extended

that deadline to 1977, and in 1978 dropped the deadline completely because of the large number of substances outstanding (203). EPA has identified some 600

active ingredients that are used in a large majority of

pesticides, but only a small fraction of these have adequate health and safety data for reregistration purposes

(2). Reregistration involves a number of steps described

in chapter 3.

Significant Judicial Decisions.—The courts have

heard a substantial number of cases concerning EPA’s

regulation of pesticides under FIFRA. Many of these

may be summarized by saying that in general the

courts have shown considerable deference to EPA’s action, since it has considerable discretion to act under

FIFRA (53,54). In particular, several court decisions

have held that the burden of proof to establish the

safety of a product remains at all times on the applicant and registrant of a product (53,54). Furthermore,

a registrant must show that the benefits from a product outweigh risks, once the agency has identified risk

to human health or the environment (54). Sometimes

the courts have upheld the agency in refusing to suspend a substance (DDT) known to cause cancer in animals and “various injuries in man” (54), and sometimes

they have upheld agency action (banning aldrin and

dieldrin) on the basis of animal test results showing

the substances caused cancer in several strains of mice

and rats (52). In addition, the courts upheld the agency

when it ordered suspension of 2,4,5-T and Silvex based

upon “inconclusive but suggestive evidence” that the

pesticides caused a statistically significant increase in

spontaneous abortions in women exposed to them

(44). Finally, the court upheld EPA’s reliance on “cancer principles” concerning use of animal tests, extrapolation from animals to humans, the presumption that

there is no safe level for carcinogens, and use of both

benign and malignant tumors in animal studies in determining cancer hazards to humans. The court noted

that industry’s scientific disagreement with these principles was not sufficient to rebut them (53).

The Toxic Substances Control Act

TSCA was enacted in 1976, and allows for the regulation of chemicals in commerce as well as before they

even enter commerce. In TSCA, Congress set the policy

●

●

●

that:

chemical manufacturers and processors are responsible for developing data about the health

and environmental effects of their chemicals;

the government regulate chemical substances

which pose an unreasonable risk of injury to

health or the environment and act promptly on

substances that pose imminent hazards; and

regulatory efforts not unduly impede industrial

innovation (15 U.S.C. 2601(b)). -

Unlike some other statutes, which are aimed at regulating exposures to toxic substances through specific

media, such as water or air, TSCA is directed toward

hazardous substances wherever they occur. Section 4

singles out for special concern substances which

present or will present significant risks of cancer,

genetic mutations, or birth defects. Under TSCA, EPA

must review data on “new” chemicals prior to their

large-scale manufacture (sec. 5), may restrict or even

ban uses of new or existing chemicals (sees. 5, 6, and

7), may require manufacturers to conduct toxicity tests

(sees. 4 and 5), and may impose certain record keeping and reporting requirements (sec. 8).

TSCA permits EPA to do two important tasks in

regulating new or existing toxic substances:

1. require testing of new or existing chemicals; and

2. restrict production and use of, or even ban, substances posing “unreasonable risks” to health or

the environment.

The treatment of new and existing substances is somewhat different (as described below) and generates

somewhat different pressures on the Agency.

TSCA is directed at chemical substances. Thus a

number of substances are excluded from TSCA regu-
217

lation, including pesticides when they are used as pesticides; tobacco and tobacco products; nuclear materials; foods, drugs, and cosmetics; and pistols,

firearms, revolvers, shells, and cartridges (15 U.S.C.

2602).

Section 8 requires EPA to compile an “inventory of

chemical substances” containing all chemicals subject

to the provisions of TSCA manufactured or imported

into the United States (15 U.S. C. 2607(b)). The initial

inventory was published on June 30, 1979, and all

chemicals that did not appear on that list and that are

not exempted from TSCA are considered “new” chemicals. The treatment of “new” and “existing” chemicals on the inventory is somewhat different, although

for both types EPA has broad authority to review

available information, require testing, and regulate

production and use.

The major criteria for EPA decisions under TSCA

is whether use of a substance 1) presents an unreasonable risk to health or the environment or 2) may present

such a risk. In deciding whether a substance poses an

unreasonable risk to health or the environment, the

agency must take into account:

● “the effects of such substance or mixture on health

and the magnitude of the exposure of human beings” to it;

Ž “the effects of such substance or mixture on the

environment and the magnitude of the exposure

of the environment to such substance of mixture”;

● “the benefits of such substance or mixture for various uses and the availability of substitutes for

such uses”; and

• “the reasonably ascertainable economic consequences of the rule, after consideration of the effect on the national economy, small business,

technological innovation, the environment, and

public health” (15 U.S.C. 2606(c)).

It is not clear that the test of “unreasonable risk,” however, is an explicit cost-benefit analysis, for at least

one major committee, the House Committee on Interstate and Foreign Commerce, indicated that assessing

the reasonableness of the risk does not require a quantitative cost-benefit analysis (212).

New Chemicals.—In general, anyone who intends

to manufacture a “new” chemical must notify EPA of

his or her intention 90 days before manufacture is to

begin. The company must submit a “remanufacture

notice” (PMN) which contains information about

chemical identity, proposed uses of the chemical, the

expected production volumes of the chemical for the

various uses, expected byproducts, estimates of the

numbers of people likely to be exposed in manufacture of the chemical, and methods for disposal (15

U.S.C. 2604(d) (1)(a), 2807(a)(2)). The PMN must also

include information on any toxicity testing that the

company has performed, although TSCA does not require that any testing be done prior to submission of

a PMN.

EPA has 90 days to review the PMN, although this

period may be extended for an additional 90 days.

EPA’s review can result in any of four actions:

1. the substance maybe manufactured without restriction;

2. the substance maybe manufactured for uses described on the PMN, but the agency can require

that it be notified if any significant new use is

considered (15 U.S.C. 2604(a)(2));

3, the manufacture, processing, use, distribution,

or disposal of the new substance may be regulated pending the development of additional information about it (15 U.S.C. 2604(e)); or

4. the manufacture, etc. of it may be regulated because it presents or will present an unreasonable risk (15 U.S.C. 2604(f)) (222).

In the PMN process, often the mere threat that EPA

might require additional testing or some kind of restrictive action is sufficient to cause a manufacturer

to remove a substance from consideration or to agree

to the proposed restrictions.

In addition, TSCA (sec. 6) gives EPA broad authority (for either new or existing substances) to regulate

the manufacture, processing, distribution in commerce, use, or disposal of a toxic chemical. If the

agency finds that “there is a reasonable basis to conclude” that any of these activities, alone or in combination, “presents or will present an unreasonable risk

of injury to health or the environment” (15 U.S. C.

2605(a)), it may regulate the substance in a number

of ways. For any substance the agency may:

• prohibit its manufacture, processing, or distribution in commerce;

● limit its amount;

● limit its uses or amounts;

• require certain labeling

. require maintenance of records and monitoring;

● prohibit or regulate any manner or method of

commercial use;

Ž prohibit or regulate its disposal; or

● require manufacturers or processors to notify EPA

of any unreasonable risks posed by it (15 U.S.C.

2605(a)).

Existing Chemicals.—For existing chemicals, EPA

can require testing and can restrict production and use.

For testing existing chemicals the statute establishes an

Interagency Testing Committee to recommend substances

to EPA for testing. Priority attention is to be given to

substances that cause or contribute to cancer, gene mutations, or birth defects (15 U.S.C. 2603(e) l(a)). TSCA

also lists a number of other factors to be considered

in making testing recommendations (see ch. 4).
278

For substances on the list, EPA synthesizes existing

exposure and hazard data to determine what data gaps

must be filled. (It may also rely on section 8 record

keeping and reporting provisions (described below) to

get exposure information. ) The aim is to try to obtain

enough information to determine whether there is an

“unreasonable risk” from the substance. If there is not

sufficient data to make this decision, the agency can

issue a regulation, using informal rulemaking, to require companies to test existing chemicals. EPA staff

regard this as an inflexible and slow procedure (343).

Testing may be required when there is insufficient

data and experience to determine whether a substance

may present an unreasonable risk of harm to health

or the environment, when testing is necessary to develop such data, and when one of two other circumstances occur: 1) the manufacture, distribution in

commerce, processing, use, or disposal of a chemical

substance or mixture “may present an unreasonable

risk of injury to health or the environment” (15 U.S.C.

2603(a)(l)(a)(i)), or 2) the substance is or will be

produced in large quantities and it will or may reasonably be anticipated to enter the environment in

large quantities or there will or may reasonably be anticipated to be significant or substantial human exposure (15 U.S.C. 2603(a)(l)(b)(i)).

After receiving required test data or any other information available if EPA finds that a chemical “presents or will present an unreasonable risk of injury to

health or the environment,” it shall by rule require one

of the actions permitted under section 6 (described

above) using the least burdensome requirements consistent with preventing unreasonable risks (15 U.S.C.

2605(a)). In addition, if the agency receives information that indicates there “may be a reasonable basis

to conclude” that a substance “presents or will present

a significant risk of serious or widespread harm to human beings from cancer, gene mutations, or birth

defects,” the administrator may initiate appropriate action under sections 5, 6, or 7 of the act. Upon finding

such risks from substances EPA has 180 days to initiate action to reduce the risks or explain why they are

“not unreasonable” (15 U.S.C. 2603(f)).

For one group of substances, polychlorinated biphenyls (PCBs), the statute specifically requires EPA

to issue rules to prescribe methods for their labeling

and disposal (15 U.S.C. 2605(e)).

Other Provisions of TSCA. —EPA also has authority to regulate “imminent hazards, ” chemicals that

present an imminent and unreasonable risk of serious

or widespread injury to health or the environment, and

are likely to occur “before a final rule under” section

6 could protect against it (15 U.S.C. 2606(f)). The statute permits EPA to initiate a civil action in Federal District Court for seizure of such substances or for judicial relief.

The agency is required under section 8 to issue rules

requiring manufacturers and processors to keep and

maintain certain records, which include information

on the chemical, its byproducts, the quantity manufactured, exposures, and reports of adverse effects. In

addition, manufacturers must report to EPA any information “which reasonably supports the conclusion

that such substance or mixture presents a substantial

risk of injury to health or the environment” (15 U.S.C.

2607(c)).

Finally, section 9 requires that if EPA finds that an

unreasonable risk from a chemical may be better prevented or reduced by another Federal agency, it shall

submit to that agency a report describing the risks and

activities that lead to the risks, and it shall request the

other agency to examine the risks and to prevent or

reduce them, if this can be done by that agency’s action. The other agency must report back to EPA within

90 days regarding its findings concerning the risks from

the referred substance (15 U.S.C. 2608).

The Resource Conservation and Recovery Act

The Resource Conservation and Recovery Act of

1976 provides for regulating the treatment, transportation, and disposal of hazardous waste. The cornerstone of the hazardous waste management system is

the identification and listing of hazardous wastes. Hazardous waste is defined as a solid waste that may cause

death or serious disease, or may present a substantial

hazard to human health or the environment if it is improperly treated, stored, transported, or disposed of

(42 U.S.C. 6903(5)). The term “solid waste” includes

solid, liquid, semisolid, or contained gaseous materials from various industrial and commercial processes.

The definition excludes solid or dissolved materials in

domestic sewage or in irrigation return flows, industrial discharges subject to the Clean Water Act or the

Atomic Energy Act, and in situ mining waste (42

U.S.C. 6903(27)).

RCRA required EPA to develop and issue criteria

for identifying the characteristics of hazardous waste

and for listing hazardous waste within 18 months of

the passage of the law.

Any waste which exhibits the characteristics of or

which is listed as a hazardous waste is regulated under RCRA3 (221).

Under RCRA, EPA sets standards concerning recordkeeping and reporting, as well as “proper” handling

and management of hazardous wastes for generators,

3Any listed waste may be delisted by rulemaking procedure, upon petition

from a particular generator or upon petition for a generic delisting. A waste

from a particular generator maybe delisted because under individual circumstances it does not meet criteria that caused it to be listed in the first place,

or the generic waste itself may be removed from RCRA lists, if EPA erred

in its original listing and the waste does not meet criteria for listing.
219

transporters, storers, and disposers of hazardous

wastes. Generators must arrange for disposal of their

wastes or shipment to a waste disposal site. Transporters must keep manifests. Transfer and disposal

must be done under certain procedures. Because regulations take this form, EPA has not set specific ambient air or water standards or effluent concentrations

for each hazardous substance, including carcinogens.

There appears to be an assumption underlying RCRA

and these regulations that once hazardous wastes are

at a disposal site they will not escape into the

environment—that “proper handling” will prevent

escape.

EPA has decided that the defining characteristics of

a hazardous waste are that it 1) pose a present or potential hazard to human health and the environment

when it is improperly managed and 2) can be measured by a quick, available, standardized test method

or reasonably detected by generators of solid waste

through their knowledge of their waste (40 CFR

261.10). The idea is to provide a quick test to identify

wastes that are capable of presenting a substantial

present or potential hazard when improperly managed.

EPA has identified four characteristics of hazardous

waste: ignitability, corrosivity, reactivity, and extraction procedure (EP) toxicity. Only the fourth is important for this report. EPA designated “extraction

procedure” as a method of chemical analysis to be used

to detect the presence of certain toxic materials in

wastes (listed at 40 CFR 261.24) at levels greater than

those indicated in the regulation. This procedure is designed to identify wastes likely to leach hazardous concentrations of toxic substances into the groundwater

under improper management (289). Constituents of

waste materials are to be extracted in a manner designed to mimic the leaching action that occurs in landfills, and this test is used to determine whether the

waste contained any toxic contaminants identified in

the National Interim Primary Drinking Water Standards under the Safe Drinking Water Act. If an extract

from a representative sample of waste contains any

contaminants (listed in table I at 40 CFR 261.23) in concentrations equal to or greater than those indicated in

the table, it exhibits EP toxicity. A person with such

material must then follow RCRA regulations for handling, transport, disposal, and record keeping. In general, substances on the EP toxicity list are regulated

under this procedure only if their EP concentrations

are no greater than 100 times the maximum levels set

by the National Interim Primary Drinking Water

Standards. EPA believes that a variety of mechanisms

in the soil and water, including dilution, adsorption,

and absorption, will serve to attenuate the toxicity

of hazardous wastes before they reach the intakes of

underground water supplies, should they be improperly disposed of and escape from a facility (289).

Some properties of solid wastes that pose a threat

to health or the environment, such as carcinogenicity, are not included in characteristics for identifying

hazardous wastes because EPA does not know of generally available testing protocols for these effects (221).

Substances are also subject to regulation under

RCRA if they are listed as hazardous wastes or are a

mixture of solid wastes and listed wastes (42 U.S. C.

6921(b)). A substance is “listed” if it:

● exhibits ignitability, corrosivity, reactivity, or EP

toxicity;

• has been found to be toxic to humans in human

or animal studies;

● is otherwise capable of causing or significantly

contributing to an increase in serious illness (in

which case it is designated an “acute hazardous

waste”); or

• contains any toxic constituents listed in Part 261,

Appendix VIII which have been shown in scientific studies to have toxic, carcinogenic, mutagenic, or teratogenic effects on human or other

life forms (such waste is designated “toxic waste”)

(221).

In May 1980 EPA published three generic lists of

wastes, based on these criteria and available scientific

and technical information, which were considered to

be hazardous and subject to RCRA subtitle C regulation: “1) hazardous waste from nonspecific sources (40

CFR 261.31); 2) hazardous waste from specific sources

(40 CFR 261.32); and 3) discarded commercial chemical products, off-specification species, containers, and

spill residues thereof (40 CFR 261.33). The discarded

commercial chemical products lists is further divided

into wastes designated as toxic wastes (40 CFR 261.33

(f)) and as acutely hazardous wastes (40 CFR 261.33

(e))” (221). These lists contain 361 commercial chemicals and 85 industrial waste processes, with others proposed as additions. Of these substances 152 are suspected carcinogens.

Either the Federal Government, or a State entity if

it has a federally approved hazardous waste program,

may enforce regulations issued under RCRA. In addition, there is a provision to permit citizen suits against

private parties and Federal or State agencies if they

are in violation of RCRA permits or regulations.

There have been no significant judicial decisions

concerning the regulation of carcinogens under RCRA.

The Comprehensive Environmental Response,

Compensation, and Liability Act

While the Resource Conservation and Recovery Act

was prospective—designed to prevent problems from

hazardous wastes in the future—the Comprehensive

Environmental Response, Compensation, and Liability Act (CERCLA), also known as “Superfund,” was
designed to address the problems of cleaning up existing hazardous waste sites.

These problems range from spills requiring immediate responses to hazardous waste dumps leaking into

the environment and posing long-term health and environmental hazards. “Hazardous substances” includes

substances specified by sections 307 and 311 of CWA,

section 3001 of RCRA (42 U.S.C. 6921), section 112

of CAA, section 7 of TSCA (15 U.S. C. 2606) and any

substance designated as hazardous under section 9602

of CERCLA (substances which “when released into the

environment may present substantial danger to the

public health or welfare or the environment . . .“).

Through this definition of “hazardous substances,”

CERCLA establishes a list of substances which, when

released in sufficient amounts, must be reported to

EPA. CERCLA section 102 sets reportable quantities

of hazardous substances at 1 pound, except when

different reportable quantities have been set under section 311(b)(4) of the Clean Water Act, and authorizes

EPA to adjust these amounts as appropriate (42 U.S.C.

9602).

Anyone in charge of an onshore or offshore facility

is required to report immediately a release of more

than the relevant-’ ’reportable quantity” of any hazardous substances to the National Response Center established under the Clean Water Act (33 U.S.C. 1251 et

seq. ) The National Response Center in turn must con- .

vey the information ‘expeditiously” to appropriate

Federal and State agencies (42 U.S.C. 9603(a)). The

site then becomes a candidate for cleanup action.

CERCLA provides EPA with “broad authority for

achieving cleanup at hazardous waste sites” (173) and

paying for the cleanup out of the Act’s “Hazardous

Substances Response Fund,” financed jointly by industry and the government (Superfund), or forcing others

“to do the cleanup by requesting an injunction in court

or by itself issuing an administrative order” (14). This

report considers only the the provisions affecting Federal regulation of carcinogens, not the many controversies surrounding the funding or administration

of Superfund.

CERCLA section 105 requires EPA to establish procedures, standards, and criteria “for both EPA and private parties for responding to releases of hazardous

waste and for cleaning up waste sites” (43). The basic

design is contained in the EPA-issued “National Contingency Plan.” This is based on a 5-step remedial response process:

1. site discovery or notification;

2. preliminary assessment and site inspection;

3. establishment of priorities for remedial action

using a scoring process (the Hazard Ranking

System (HRS)) for identifying sites to be included in the National Priorities List (NPL);

4. remedial investigation and feasibility study;

5. remedial design and construction (327).

HRS prescribes the method to be used to evaluate

the relative potential of uncontrolled hazardous substance facilities to cause health or safety problems, or

ecological or environmental damage. HRS is in part

used to set cleanup priorities. HRS assigns scores for

potential harms from migration of hazardous substances away from the site by means of groundwater,

surface water or air, from explosion or fires, and from

human contact. All assignments of scores must take

into account “waste characteristics, ” which include

waste quantities, toxicity, and persistence.

Carcinogens are assigned the highest toxicity scores,

meaning they are among the most toxic substances

according to the ranking system, and many of them

tend to be judged quite persistent, thus less likely to

biodegrade in the environment, according to the system (40 CFR 300, App, A, pp. 710-712). EPA has developed a quantitative system for deciding the reportable quantities of carcinogens based on the quality of

evidence for the carcinogenicity of a substance and its

potency. This procedure is described in chapter 4 under “Agency Actions.”

Once a site has been identified for cleanup the

appropriate agency (a Federal or State governmental

entity or private party) must investigate the site and

then remedy the problem. In studying the feasibility

of cleanup, rather than proposing some target standards to answer the question, “How clean is clean?”

EPA recommended that the lead agency consider at

least five alternative cleanup strategies:

1.

2.

3.

4.

5.

an alternative that considers treatment or disposal at an off-site facility, i.e., removal of the

problem wastes;

an alternative that attains applicable or relevant

Federal or State environmental and health

standards;

an alternative that exceeds such standards;

an alternative that does not attain applicable or

relevant standards, but will “reduce the likelihood of present or future threats to public

health;” and

a no-action alternative (327).

The selection of remedy, however, is being reevaluated in light of the 1986 Superfund Amendments and

Reauthorization Act (SARA), section 121, which requires that the degree of cleanup at superfund sites “assures the protection of human health and the environment” and achieves compliance with standards

established under other Federal and State environmental laws. Other sections of SARA are discussed in

chapter 3.
Appendix B

Chemicals Listed in Annual Report on

Carcinogens and NCI/NTP Test Results

Table B-l.—Chemicals Listed in Annual Report on Carcinogens

CAS No. -

--- . .

53-96-3

107-13-1

23214 -92-8

1402 -68-2

82-28-O

117-79-3

92-67-1

61-82-5

90-04-0

134-29-2

140-57-8

7440-38-2

1327 -53-3

1332 -21-4

446-86-6

71-43-2

92-87-5

98-07-7

7440 -41-7

494-03-1

542-88-1

154-93-8

55-98-1

7440-43-9

56-23-5

305-03-3

95-83-O

13010-47-4

67-66-3

7440 -47-3

NA

120-71-8

135-20-6

14901 -08-7

50-18-0

4342 -03-4

50-29-3

117-81-7

391-41-7

95-80-7

96-12-8

106-93-4

91-94-1

107-06-2

1464 -53-5

64-67-5

Substance name CAS NO. Substance name

2-AcetylaminofIuorene

Acrylonitrile

Adriamycin

AfIatoxins

l-Amino-2-methylanthraquinone

2-Aminoanthraquinone

4-Aminobiphenyl

Am it role

o-Anisidine

and o-Anisidine Hydrochloride

Aramite

Arsenic

and certain arsenic compounds

Asbestos

Azathioprine

Benzene

Benzidine

Benzotrichloride

Beryllium and certain beryllium

compounds

N, N-bis (2-chloroethyl) -2-naphthylamine

(chlornaphazine)

Bis (chloromethyl) ether and technical

grade chloromethyl methyl ether

Bischloroethyl nitro-sourea

1,4-Butanediol dimethy-sulfonate

(myleran)

Cadmium and certain cadmium

compounds

Carbon tetrachloride

Chlorambucil

4-Chloro-o-phenylene-diamine

1-(2-Chloroethyl)-3-cyclohexyl-1-

nitrosourea (CCNU)

Chloroform

Chromium and certain chromium

compounds

Coke oven emissions

p-Cresidine

Cupferron

Cycasin

Cyclophosphamide

Dacarbazine

DDT

Di(2-ethylhexyl)phthalate

2,4-Diaminoanisole sulfate

2,4-Diaminotoluene

1,2-Dibromo-3-chloropropane

1,2-Dibromoethane (EDB)

3,3’ -Dichlorobenzidine

1,2-Dichloroethane

Diepoxybutane

Diethyl sulfate

2602-46-2

1937-37-7

106-89-8

50-50-0

50-28-2

53-16-7

57-63-6

72-33-3

96-45-7

75-21-8

50-00-0

NA

118-74-1

680-31-9

302-01-2

10043-93-2

122-66-7

9004 -66-4

NA

143-50-0

301-04-2

7446-27-7

58-89-9

319-85-7

608-73-1

NA

148-82-3

NA

74-88-4

75-55-8

101-61-1

101-14-4

101-77-9

443-48-1

90-94-8

2385 -85-5

505-60-2

91-59-8

7440-02-0

139-13-9

99-59-2

Direct Blue 6

Direct Black 38

Epichlorohydrin

Estrogens—conjugated:

a) Estradiol benzoate

b) Estradiol monopalmitate

Estrogens—not conjugated:

a) Estradiol 17 beta

Estrogens—not conjugated:

b) Estrone (metabolize of Estradiol 17

beta)

Estrogens—not conjugated:

c) Ethinylestradiol

Estrogens—not conjugated:

d) Mestranol

Ethylene thiourea

Ethylene oxide

Formaldehyde

Hematite underground mining

Hexachlorobenzene

Hexamethylphosphoramide

Hydrazine &

Hydrazine Sulfate

Hydrazobenzene

Iron dextran complex

Isopropyl alcohol manufacture (strongacid process)

Kepone (Chlordecone)

Lead acetate

Lead phosphate

Lindane (y-hexachlorocyclohexane)

Lindane (b-Hexachlorocyclohexane)

Lindane (Hexachlorocyclohexane)

Manufacture of auramine

Melphalan

Methoxsalen with ultra-violet A therapy

(PUVA)

Methyl iodide

2-Methylaziridine (propyleneimine)

4,4’ -Methylenebis (N, N-dimethyl)

benzenamine (Michler’s base)

4,4’ -Methylenebis (2-chloroaniline)

(M BOCA)

4,4’ -Methylenediani line and its

dihydrochloride

Met ronidazole

Michler’s ketone

Mirex

Mustard gas

2-Naphthylamine

Nickel and certain nickel compounds

Nitrilotriacetic acid

5-N itro-o-anisidine

continued on next pag e

221
222

3,3’ -D~methoxybenzidi ne

Dimethyl sulfate

4-Dimethylaminoazobenzene

3,3’ -Dimethylbenzidine

Dimethylcarbamoyl chloride

1,l-Dimethylhydrazine

1,4-Dioxane

N-Nit rosodiethylamine

N-Nit rosodimethylamine

p-Nit rosodiphenylami ne

N-Nit rosomethylvi nylamine

N-Nit rosomorphol ine

N-Nit rosonornicotine

N-Nit rosopiperidi ne

N-Nit rosopyrrol idine

N-Nit rososarcosine

Norethisterone

Oxymetholone

PAHs:

a) Benz (a) anthracene

b) Benzo (b) fluoranthene

c) Benzo (a) pyrene

d) Dibenz (a,h) acridine

e) Dibenz (a,j) acridine

f) Dibenz (a,h) anthracene

g) 7H-Dibenzo (c,g) carbazole

h) Dibenzo (a,h) pyrene

i) Dibenzo (a,i) pyrene

j) Indeno (1,2,3-cd) pyrene

Phenacetin and analgesic mixti

containing phenacetin

Phenazopyridine hydrochloride

Phenytoin and sodium salt of

phenytoin

Polybrominated biphenyls

Polychlorinated biphenyls

55-86-7

79-46-9

759-73-9

684-93-5

924-16-3

621-64-7

1116-54-7

671-16-9

366-70-1

57-83-O

1120 -71-4

57-57-8

51-52-5

50-55-5

NA

81-07-2

394-59-7

7446-34-6

8007 -45-2

1883-66-4

95-06-7

1746-01-6

62-55-5

62-55-5

1314 -20-1

584-84-9

95-53-4

636-21-5

8001 -35-2

Jres 88-06-2

126-72-7

52-24-4

51-79-6

75-01-4

Table B-1 .—Chemicals Listed in Annual Report on Carcinogens—Continued

CAS No. Substance name CAS No. Substance name

56-53-1 Diethvlstilbestrol (DES) 1836-75-5

119-90-4

77-78-1

60-11-7

119-93-7

79-44-7

57-14-7

123-91-1

55-18-5

62-75-9

156-10-5

4549-40-0

59-89-2

16543 -55-8

100-75-4

930-55-2

13256 -22-9

68-22-4

434-07-1

56-55-3

205-99-2

50-32-2

226-36-8

226-36-8

53-70-3

194-59-2

189-64-0

189-55-9

193-39-5

62-44-2

136-40-3

57-41-0

36355-01-8

1336-36-3

SOURCE: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Fourfh Annual Reporf on Carcinogens, 1985.

Table B-2.—NCUNTP Test Results

Nitrofen

Nitrogen mustard

2-Nitropropane

N-N troso-N-ethylurea

N-Nitroso-N-methylurea

N-Nitrosodi-n-butylamine

N-Nitrosodi-n-propylamine

N-Nitrosodiethanolamine

Procarbazine

Procarbazine Hydrochloride

Progesterone

1,3-Propane sultone

beta-Propiolactone

Propylthiouracil

Reserpine

Rubber industry (certain occupations)

Saccharin

Safrole

Selenium sulfide

Soots, tars, and mineral oils

Streptozotocin

Sulfallate

2,3,7,8-Tetrachlorodi-benzo-p-dioxin (TCDD)

Thioacetamide

Thiourea

Thorium dioxide

Toluene diisocyanate

o-Toluidine

o-Toluidine Hydrochloride

Toxaphene

2,4,6-TrichIorophenol

Tris (2,3-dibromopropyl)phospate

Tris(1-aziridinyl)phosphine sulfide

Urethane

Vinyl chloride

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

968-81-0

7008-42-6

9002-18,0

116-06-3

309-00-2

107-05-1

57-06-7

2835-39-4

82-28-O*

119-34-6

17026-81-2

121-66-4

6109-97-3

11 7-79-3*

2432-99-7

7177-48-2

Acetohexamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Acronycine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Agar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Aldicarb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Aldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Allyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Allyl isothiocyanate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Allyl isovalerate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

l-Amino-2-methy lanthraquinone . . . . . . . . . . . . . . . . . . 1978

4-Amino-2-nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

3-Amino-4 -ethoxyacetanilide . . . . . . . . . . . . . . . . . . . . . 1978

2-Amino-5-nitrothiazole . . . . . . . . . . . . . . . . . . . . . . . . . 1978

3-Amino-9-ethyIcarbazole hydrochloride . . . . . . . . . . . 1978

2-Aminoanthraquinone. . . . . . . . . . . . . . . . . . . . . . . . . . 1978

11-Aminoundecanoic acid . . . . . . . . . . . . . . . . . . . . . . . 1982

Ampicillin trihydrate . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

neg.

two

neg.

neg.

one

equiv.

one

two

three

one

one

one

four

three

one

equiv.

NN N N

PP II

NN N N

NN N N

EE P N

NN E E

PE N N

PN N P

PP N P

PE N N

NN P N

PN N N

PP P P

PI P P

PN E N

EN N N

[050]

[230]

[136]

[21]

[73]

[234]

[253]

[111]

[94]

[1 12]

[53]

[93]

[144]

[216]

[318]

KEY: P–phosphate; N—negative; l—inadequate; E—equivocal; NA—not available.

“Indicates listing in Annual f?epofl on Carcinogens. continued on next page
223

Table B-2.-NCIINTP Test Results—Continued

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

101-05-3 Anilazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978 neg. NN N N [104]

142-04-1 two [1 30]

134-29-2* [89]

20265-97-8

118-92-3

11097 -69-1

12001 -29-5

12001 -29-5

12001 -29-5

12182 -73-5

50-81-7

8003 -03-0

320-67-2

86-50-0

103-33-3

71 -43-2*

119-53-9

105-11-3

95-14-7

140-11-4

2185 -92-4

108-60-1

80-05-7

106-99-0

85-68-7

128-37-O

6459-94-5

1936 -15-8

569-61-9

2602-46-2’

1937-37-7*

16071 -86-6

2475 -45-8

2832 -40-8

842-07-9

128-66-5

156-62-7

105-60-2

133-06-2

77-65-6

133-90-4

57-74-9

143-50-0*

115-28-6

63449-39-8

63449-39-8

56802 -99-4

140-49-8

563-47-3

5131 -60-2

95-83-O*

95-79-4

3165-93-3

61702 -44-1

95-74-9

106-47-8

108-90-7

510-15-6

KEY: P—phosphate, N—negative, l—inadequate, E—equivocal; NA—not available

“Indicates listing In Annual Report on Carcinogens

a

Tested in hamsters.

Aniline hydrochloride. . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

o-Anisidine hydrochloride (2-Methoxyaniline) . . . . . . 1978

p-Anisidine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . 1978

o-Anthranilic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Aroclor 1254 (polychlorinated biphenyls) . . . . . . . . . . 1978

Asbestos –Chrysotile (IR) . . . . . . . . . . . . . . . . . . . . . . 1985

Asbestos –Chrysotile (SR) . . . . . . . . . . . . . . . . . . . . . 1985

Asbestos —Chrysotile (IR) + Dimethyl Hydrazine . . 1985

Asbestos, Amosite. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

L-Ascorbic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

Aspirin, Phenacetin, and Caffeine (APC) . . . . . . . . . . 1978

5-Azacytidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Azinphosmethyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Azobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Benzoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

p-Benzoquinone dioxime. . . . . . . . . . . . . . . . . . . . . . . . 1979

l,2,3-Benzotriazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Benzyl acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

2-Biphenylamine hydrochloride . . . . . . . . . . . . . . . . . . 1982

bis(2-Chloro-l -methylethyl) ether . . . . . . . . . . . . . . . . . 1982

1979

Bisphenol A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

l,3-butadiene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3984

Butyl benzyl phthalate. . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Butylated hydroxytoluene (BHT) . . . . . . . . . . . . . . . . . 1979

C.I. Acid Red 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

C.i. Acid Orange10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Cl. Basic Red 9 Monohydrochloride. . . . . . . . . . . . . . 1986

Cl. Direct Blue6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Cl. Direct Black38 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Cl. Direct Brown 95. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Cl, Disperse Blue 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Cl. Disperse Yellow3 . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Cl. Solvent Yellow 14 . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

C.l. Vat Yellow4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Calcium cyanamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Caprolactam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Captan . . . . . . . . . . . . . . . . . . . . . . . .. ... ... ...OO .” 1977

Carbromal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Chloramben . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

Chlordane (technical grade) . . . . . . . . . . . . . . . . . . . . . 1977

Chlordecone (kepone) . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Chlorendic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Chlorinated paraffins: C23,43Vo chlorine . . . . . . . . . 1986

Chlorinated paraffins: C12,600/O chlorine . . . . . . . . . 1986

Chlorinated trisodium phosphate . . . . . . . . . . . . . . . . NA

4-(Chloroacetyl) acetanilide . . . . . . . . . . . . . . . . . . . . . . 1979

3-Chloro-2-methylproPene . . . . . . . . . . . . . . . . . . . . . . . 1986

4-Chloro-m-phenylenediamine . . . . . . . . . . . . . . . . . . . 1978

4-Chloro-o-phenylenediamine . . . . . . . . . . . . . . . . . . . . 1978

5-Chloro-o-toluidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

4-Chloro-o-toluidine hydrochloride. . . . . . . . . . . . . . . . 1979

2-Chloro-p-phenylenediamine sulfate . . . . . . . . . . . . . 1978

3-Chloro-p-toluidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

p-Chloroaniline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Chiorobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

Chlorobenzilate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

four

equiv.

neg.

equiv.

one

neg.

inad.

neg.

neg.

equiv.

one

equiv.

two

four

neg.

one

equiv.

two

one

two

neg.

equiv.

two

one

neg.

neg.

neg.

four

two

two

two

two

two

two

one

neg.

neg.

two

neg.

one

two

four

three

one

four

inad.

neg.

four

two

four

two

two

neg.

neg.

equiv.

equiv.

two

PPN N

PPP P

ENN N

NNN N

EE/ /

PN/ /

NN/ /

11/ /

N

a Na / /

NNN N

NEN N

III P

ENN N

PPN N

PPF P

NNN N

NPN N

EEN E

ENP P

NNE P

//P P

NN/ /

ENN N

//P P

IPN N

NNN N

NNN N

NNN N

PPP P

PP/ /

PP/ /

IPI I

PPE N

PNN P

PPN N

NNP N

NNN N

NNN N

NNP P

NNN N

NNE P

NNP P

PPP P

PPP N

NEP E

PPP P

I IN N

NNN N

PPP P

PNN P

PPP P

NNP P

NNP P

NNN N

NNN N

ENE E

ENN N

EEP P

[116]

[36]

[38]

[295a]

[295b]

[295c]

[249]

[247]

[671

[42]

[691

[154]

[289]

[204]

[791]

[88]

[250]

[233]

[239]

[191]

[215]

[288]

[213]

[150]

[220]

[211]

[285]

[108]

[108]

[108]

[299]

[224

[226]

[134]

[163]

[214]

[15]

[173]

[ 8 ]

[NA]

[304]

[305]

[308]

[294]

[177]

[300]

[85]

[63]

[187]

[165]

[113]

[145]

[189]

[261]

[75]

continued on next page
224

Table B.2.—NCI/NTP Test Results-Continued

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

124-48-1 Chlorodibromomethane. . . . . . . . . . . . . . . . . . . . . . . . . 1985 NN E P [282]

107-07-3

999-81-5

67-66-3*

6959-47-3

6959-48-4

76-06-2

1897-45-6

113-92-8

94-20-2

87-29-6

1420-04-8

56-72-4

102-50-1

120-71-8*

135-20-6’

21739-91-3

69-65-8

5160-02-1

72-55-9

50-29-3

1163-19-5

103-23-1

11 7-81-7*

72-56-O

131-17-9

39156-41 -7*

95-80-7”

6358-85-6

333-41-5

262-12-4

96-12-8*

106-93-4*

1067-33-0

609-20-1

106-46-7

95-50-1

33857 -26-O

75-43-3

107-06-2”

75-09-2

78-87-5

542-75-6

62-73-7

115-32-2

60-57-1

DIES ELFUEL

DIESELFUEL

101-90-6

60-51-5

54150-69-5

91-93-0

868-85-9

597-25-1

120-61-6

2-Chloroetharrol (ethylene chlorohydrin). . . . . . . . . . . 1985

2-Chloroethyltrimethy lammonium chloride . . . . . . . . 1979

Chloroform. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

2-Chloromethylpy ridine hydrochloride . . . . . . . . . . . . 1979

3-Chloromethylpy ridine hydrochloride . . . . . . . . . . . . 1978

Chloropicrin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Chlorothalonil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Chlorpheniramine maleate . . . . . . . . . . . . . . . . . . . . . . 1986

Chlorpropamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Cinnamyl anthranilate . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

Clonitralid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Coumaphos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

m-Cresidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

p-Cresidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Cupferron. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Cytembena. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1981

D-Mannitol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

D&CRed NO. 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

P,P’-DDE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

DOT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Decabromodiphenyl oxide . . . . . . . . . . . . . . . . . . . . . . 1986

Di(2-Ethylhexyl) adipate . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Di(2-Ethylhexyl) phthalate . . . . . . . . . . . . . . . . . . . . . . . 1982

Di(P-Ethylphenyl) dichloroethane . . . . . . . . . . . . . . . . . 1979

Diallyl phthalate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

1985

2,4-Diaminoanisole sulfate . . . . . . . . . . . . . . . . . . . . . . 1979

2,4-Diaminotoluene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Diarylanilide Yellow . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Diazinon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Dibenzo-p-dioxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

1,2-Dibromo-3-chloropropane (DBCP) . . . . . . . . . . . . . 1978

1982

l,2-Dibromoethane (ethylene dibromide) . . . . . . . . . . 1978

1982

Dibutyltin diacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

2,6-Dichloro-p-phenylenediamine . . . . . . . . . . . . . . . . . 1982

1,4-Dichlorobenzene. . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

1,2-Dichlorobenzene (o-dichlorobenzene) . . . . . . . . . . 1985

2,7-dichlorodibenzo-p-dioxin (DODD) . . . . . . . . . . . . . . 1979

1,1-Dichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1,2-Dichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Dichloromethane (methylene chloride) . . . . . . . . . . . . 1986

1,2-Dichloropropane (propylene dichloride) . . . . . . . . 1986

1,3-dichloropropene (Telonell) . . . . . . . . . . . . . . . . . . . 1985

Dichlorvos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

Dicofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Dieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1978

Diesel fuel marine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

JPnaval fuel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Diglycidyl resorcinol ether (DGRE) . . . . . . . . . . . . . . . 1983

Dimethoate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

2,4-Dimethoxyaniline hydrochloride . . . . . . . . . . . . . . 1979

3,3’-Dimethoxybenzidine-4,4’-diisocyanate . . . . . . . . . 1979

Dimethyl hydrogen phosphite . . . . . . . . . . . . . . . . . . . 1985

Dimethyl morpholinophos-phosphoramidate . . . . . . . 1986

Dimethyl terephthalate . . . . . . . . . . . . . . . . . . . . . . . . . 1979

one

neg.

neg.

three

neg.

three

inad.

two

neg.

neg.

three

equiv.

neg.

two

four

four

two

neg.

one

two

neg.

two

two

four

equiv.

equiv.

equiv.

four

three

neg.

neg.

neg.

four

four

four

four

inad.

two

three

neg.

equiv.

equiv.

four

four

two

three

neg.

one

equiv.

neg.

equiv.

neg.

four

neg.

neg.

two

one

two

equiv.

NNN N

NNN N

P/P P

NNN N

PEP P

I IN N

PPN N

NNN N

NNN N

PNP P

NEI N

NNN N

PPI N

PPP P

PPP P

PPN N

NNN N

PEN N

NNP P

NNN N

PPE N

NNP P

PPP P

NNN E

//E E

NE/ /

PPP P

PPN P

NNN N

NNN N

NNN N

PPP P

PPP P

PPP P

PPP P

NIN N

NNP P

PNP P

NNN N

NNE N

NEN E

PPP P

PPP P

NEP P

PPI P

NNN N

NNP N

NNE N

NN/ /

IIE E

//N N

PPP P

NNN N

NNN N

PPN N

PEP P

PPN N

NNE N

1275]

158]

NA

!178]

’95]

:65]

’41]

‘317]

’45]

196]

:91]

[96]

~oq

~42]

100]

‘207]

‘236]

:225]

131]

131]

“309]

212]

217]

156]

242]

284]

84]

162]

30]

137]

122]

’28]

206]

86]

210]

183]

219]

319]

255]

123]

66]

55]

306]

263]

269]

10]

90]

21]

22]

310a]

310b]

257]

4]

171]

128]

287]

298]

KEY: P—phosphate; N—negative; l—inadequate; E—equivocaL NA—not available.

‘Indicates listing in Armua/ Repoff on Carcinogens. continued on next page
225

Table B-2.—NCUNTP Test Results—Continued

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

m3-37-l

, .

121-14-2

123-91-1 ●

78-34-2

142-46-1

15356 -70-4

316-42-7

115-29-7

72-20-8

134-72-5

229-66-79-6

536-33-4

140-88-5

20941 -65-5

150-38-9

97-53-o

2783-94-O

55-38-9

2164 -17-2

140-56-7

105-87-3

9,000 -30-0

9,000-01-5

68916-39-2

33229-34-4

2784 -94-3

2871 -01-4

76-44-8

57653-85-7

67-72-1

70-30-4

122-66-7*

148-24-3

21416 -87-5

75-47-8

3458-22-8

78-59-1

3778-73-2

303-43-4

19010-66-3

58-89-9

434-13-9

9,000-40-2

1634 -78-2

121-75-5

108-78-1

72-43-5

80-62-6

298-00-0

129-15-7

101-61-1 ●

13552-44-8*

3~5-~a-4

90-94-8’

150-68-5

1465-25-4

KEY: P—phosphate; N—negative; I—inadewate; E—equivocal; NA—not available

“Indicates listing in Annual Reporf on Carcinogens.

Dimethylvinyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

2,4-Dinitrotoluene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1,4-Dioxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Dioxathion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

2,5-Dithiobiurea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

DL-Menthol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Emetine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Endosulfan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Endrin . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . . . . . . . . 1979

Ephedrine sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Estradiol mustard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Ethionamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Ethyl acrylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Ethyl tellurac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Ethylenediamine tetraacetic acid (EDTA). . . . . . . . . . 1977

Eugenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

FD&C Yellow No.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1981

Fenthion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Fluometuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

Formulated fenaminosulf . . . . . . . . . . . . . . . . . . . . . . . 1978

Geranyl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Guar gum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Gum arabic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Hamamelis Water (witch hazel) . . . . . . . . . . . . . . . . . . 1984

HCBlue2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

HCBlue 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

HCRed 3...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Heptachlor, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin . . . . . . . . . . . . 1980

1980

Hexachloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Hexachlorophene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Hydrazobenzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

8-Hydroxyquinoline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

ICRF-159. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Iodoform (triiodomethane). . . . . . . . . . . . . . . . . . . . . . . 1978

lPD(3,3’-lminobis-l-propanol dimethanesulfonate

(ester)hydrochloride) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Isophorone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Isophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

Lasiocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Lead dimethyldithiocarbamate . . . . . . . . . . . . . . . . . . . 1979

Lindane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

Lithocholic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Locust bean gum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Malaoxon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Malathion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1979

Melamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

Methoxychlor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Methyl methacrylate . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Methyl parathion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

2-Methyl-l-nitroanthraquinone . . . . . . . . . . . . . . . . . . . 1978

4,4’-Methylenebis (N,N-dimethyl) benzenamine . . . . . 1979

4,4’-Methylenedianiline dihydrochloride . . . . . . . . . . . 1983

Mexacarbate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Michler’s ketone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Monuron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

N-(l-naphthyl) ethylenediamine dihydrochloride . . . . 1979

four

two

four

neg.

equiv.

neg.

inad.

inad.

neg.

neg.

two

neg.

four

equiv.

neg.

equiv.

neg.

equiv.

equiv.

neg.

neg.

neg.

neg.

neg.

neg.

three

equiv.

two

three

neg.

two

neg.

three

neg.

two

neg.

equiv.

one

two

two

neg.

neg.

neg.

neg.

neg.

neg.

neg.

one

neg.

neg.

neg.

four

three

four

neg.

four

one

neg.

PPP P

PPN N

PPP P

NNN N

NNN E

NNN N

111 1

A: k :

NN N N

NN P P

NN N N

PP P P

EN E E

NN N N

NN E E

NN N N

NN E N

NN E N

NN N N

NN N N

NN N N

NN N N

NN N N

NN N N

EP P P

NN E l

NE P P

EP P P

// N N

NN P P

NN / /

PP N P

NN N N

NP N P

NN N N

EE E E

PN E N

NP N P

PP / /

NN N N

NN N N

NN N N

NN N N

NN N N

NN N N

NN / /

PN N N

NN N N

NN N N

NN N N

PP P P

PP E P

PP P P

NN N N

PP P P

PN N N

NN N N

[316]

[54]

[80]

[125]

[132]

[98]

[43]

[62]

[12]

[307]

[59]

[46]

[259]

[152]

[11]

[223]

[208]

[103]

[195]

[101]

[252]

[229]

[227]

[286]

[293]

[271]

[281]

[9]

[198]

[202]

[68]

[40]

[92]

[276]

[78]

[110]

[18]

[291]

[32]

[39]

[151]

[14]

[175]

[221]

[135]

[24]

[192]

[245]

[35]

[314]

~;;;]

[186]

[248]

[147]

[181]

[266]

[168]

continued on next page
226

Table B-2.—NCI/NTP Test Results—Continued

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

109-69-3

—— —— -

N-Butyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986 NN N N [312]

86-30-8’

101-54-2

2243-62-1

139-94-6

99-59-2*

99-56-9

99-55-8

1777-84-0

5307-14-2

602-87-9

619-17-0

94-52-O

1836-75-5’

88-57-7

504-88-1

156-10-5

102-96-5

1212-29-9

105-55-5

139-13-9*

18662-53-8*

18682-53-8*

101-80-4

2058-46-0

56-38-2

76-01-7

82-68-8

136-40-3”

3546-10-9

834-28-6

108-95-2

63-92-3

103-85-5

89-25-8

624-18-0

61-76-7

90-43-7

13171 -21-6

13366-73-9

85-44-9

88-96-o

1918-02-1

51-03-6

120-82-7

1955-45-9

67774-32-7

366-70-1 ●

952-23-8

121-79-9

115-07-1

75-56-9

98-96-4

58-14-9

50-55-5”

7446-34-6*

N-Nitr_osodipheny lamine . . . . . . . . . . . . . . . . . . . . . . . . 1979

N-Phenyl-p-pheny lenediamine . . . . . . . . . . . . . . . . . . . 1978

l,5-Naphthalenediamine . . . . . . . . . . . . . . . . . . . . . . . . 1978

Nithiazide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

5-Nitro-o-anisidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

4-Nitro-o-phenylenediamine . . . . . . . . . . . . . . . . . . . . . 1979

5-Nitro-o-toluidine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

3-Nitro-p-acetophenetide . . . . . . . . . . . . . . . . . . . . . . . . 1979

2-Nitro-p-phenylenediamine . . . . . . . . . . . . . . . . . . . . . 1979

5-Nitroacenaphthene . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

4-Nitroanthranilic acid . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

5(6)-Nitrobenzimidazole . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Nitrofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1979

l-Nitronaphthalene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

3-Nitropropionic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

p-Nitrosodiphenylamine. . . . . . . . . . . . . . . . . . . . . . . . . 1979

beta-Nitrostyrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

N,N’-Dicyclohexylthiourea . . . . . . . . . . . . . . . . . . . . . . . 1978

N,N’-Diethylthiourea. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

NTA(Nitrilotriacetic acid) . . . . . . . . . . . . . . . . . . . . . . . 1977

Trisodium nitrilotriacetate monohydrate . . . . . . . . . . 1977

Trisodium nitrilotriacetate monohydrate . . . . . . . . . . 1977

4,4’-Oxydianiline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

Oxytetracycline hydrochloride NA

Parathion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Pentachloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

Pentachloronitrobenzene. . . . . . . . . . . . . . . . . . . . . . . . 1978

NA

Phenazopyridine hydrochloride . . . . . . . . . . . . . . . . . . 1978

Phenesterin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Phenformin hydrochloride. . . . . . . . . . . . . . . . . . . . . . . 1977

Phenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

Phenoxybenzamine hydrochloride . . . . . . . . . . . . . . . . 1978

l-Phenyl-2-thiourea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

l-Phenyl-3-methyl-5-pyrazolone . . . . . . . . . . . . . . . . . . . 1978

p-Phenylenediamine dihydrochloride . . . . . . . . . . . . . 1979

Phenylephrine hydrochloride . . . . . . . . . . . . . . . . . . . . NA

o-Phenylphenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Phosphamidon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Photodieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

Phthalic anhydride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Phthalimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Picloram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Piperonyl butoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Piperonyl sulfoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Pivalolactone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Polybrominated biphenyl mixture (Firemaster FF-l). 1983

Procarbazine hydrochloride . . . . . . . . . . . . . . . . . . . . . 1977

Proflavin hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . 1977

propyl gallate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Propylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

l,2-Propylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1985

Pyrazinamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Pyrimethamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Reserpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Selenium sulfide (twice) . . . . . . . . . . . . . . . . . . . . . . . . 1980

NA

neg.

two

neg.

three

two

three

neg.

two

one

one

three

neg.

two

three

two

neg.

equiv.

two

neg.

neg.

two

four

equiv.

two

four

equiv.

equiv.

two

neg.

neg.

three

three

neg.

neg.

four

neg.

neg.

neg.

neg.

neg.

equiv.

neg.

neg.

neg.

equiv.

neg.

one

two

four

four

equiv.

equiv.

neg.

four

inad.

inad.

three

three

neg.

PPN N

NNN N

NPP P

NPP E

PPE P

NNN N

NNP P

NNP N

NNN P

PPN P

NNN N

NNP P

EPP P

NNP P

NNN N

ENN N

PNP N

NNN N

NNN N

PPN N

PPP P

EEN N

PP/ /

PPP P

EEN N

EEN N

ENP P

NNN N

//N N

PPN P

NPP P

NNN N

NNN N

PPP P

NNN N

NNN N

NNN N

NNN N

//N N

EEN N

NNN N

NNN N

NNN N

NEN N

NNN N

NNP N

PPN N

PPP P

PPP P

ENE E

EN E N

NNN N

PPP P

NNN I

NNI N

PNP P

PPN P

//N N

~64]

[82]

~43]

~46]

~271

~80]

~071

~331

~6!31

~18]

~09]

~171

[26]

~84]

[64]

[52]

~ w ]

~70]

[56]

~491

[6z4

[6b]

[6c]

[205]

[315]

[70]

[232]

[61]

[325]

[991

[60]

[7]

[203]

[72]

~48]

~41]

~74]

[322]

[301]

~6]

~7]

~ 5 q

~61]

[231

~20]

~24]

~40]

[244]

~ q

[5]

[240]

[272]

[2671

[0481

[771

~93]

~94]

~971

KEY: P—phosph?te; N—negative; l—inadequate; E—equivocaLNA—not available.

“Indicates llsting in ArmualReport on Carcinogens. conthuedon next page
227

Table B-2.—NCI/NTP Test Results—Continued

Test results Results Technical

Number Rats Mice report

CAS No. Substance Year positive MF M F number

SELSUN

148-18-5

7772 -99-8

100-42-5

1596-84-5

95-06-7”

127-69-5

77-79-2

80-08-0

39300-88-4

2438-88-2

1746-01 -6*

72-54-8

630-20-6

79-34-5

127-18-4

961-11-5

97-77-8

55566-30-8

139-65-1

789-61-7

13463 -67-7

1156 -19-0

64-77-7

26471 -62-5

15481 -70-6

6369-59-1

636-21-5’

8001-35-2”

79-00-5

71-55-6

79-01-6

75-69-4

88-06-2*

1582 -09-8

137-17-7

512-56-1

2489-77-2

76-87-9

78-42-2

126-72-7”

52-24-4*

73-22-3

100-40-3

75-35-4

1330-20-7

17924-92-4

137-30-4

Selsun . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

Sodium diethyldithiocarbamate . . . . . . . . . . . . . . . . . . 1979

Stannous chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Succinic acid 2,2-dimethyl-hydrazide (Daminozide) . 1978

Sulfallate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Sulfisoxazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

3-Sulfolene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

4,4’-Sulfonyldianiline (Dapsone) . . . . . . . . . . . . . . . . . . 1977

Taragum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

2,3,5,6-Tetrachloro-4-nitro-anisole . . . . . . . . . . . . . . . . . 1978

2,3,7,8-Tetrachlorodibenzo-p-dioxin . . . . . . . . . . . . . . . 1982

1982

2,3,7,8-Tetrachlorodibenzo-p-dioxin + (PDMBA) . . . . 1982

Tetrachlorodiphenylethane (TEE) . . . . . . . . . . . . . . . . . 1978

1,1,1,2-Tetrachloroethane . . . . . . . . . . . . . . . . . . . . . . . 1983

1,1,2,2-Tetrachloroethane . . . . . . . . . . . . . . . . . . . . . . . 1978

Tetrachloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1987

1977

Tetrachlorvinphos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Tetraethylthiuram disulfide . . . . . . . . . . . . . . . . . . . . . . 1979

Tetrakis (hydroxymethyl) phosphonium sulfate. . . . . NA

4,4’-Thiodianiline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

beta-Thioguanidine deoxyriboside . . . . . . . . . . . . . . . . 1978

Titanium dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Tolazamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Tolbutamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1977

2,4-&2,6-Toluene diisocyanate . . . . . . . . . . . . . . . . . . . 1986

2,6-Toluenediamine dihydro-chloride . . . . . . . . . . . . . . 1980

2,5-Toluenediamine sulfate . . . . . . . . . . . . . . . . . . . . . . 1978

o-Toluidine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . 1979

Toxaphene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

1,1,2-Trichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

1,1,1-Trichloroethane (methyl chloroform) . . . . . . . . . 1977

Trichloroethylene (without epichlorohydrin) . . . . . . . 1976

NA

1986

Trichlorofluoromethane . . . . . . . . . . . . . . . . . . . . . . . . . 1978

2,4,6-Trichlorophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Trifluralin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

2,4,5-Trimethylaniline. . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Trimethylphosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Trimethylthiourea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1979

Triphenyitin hydroxide . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

Tris(2-Ethylhexyl)phosphate . . . . . . . . . . . . . . . . . . . . . 1984

Tris(2,3-Dibromopropyl)phosphate . . . . . . . . . . . . . . . . 1978

Tris(Aziridinyl)-phosphine sulfide . . . . . . . . . . . . . . . . . 1978

L-Tryptophan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1978

4-Vinylcyclohexene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986

Vinylidene chloride (l,l-dichloroethylene) . . . . . . . . . 1982

Xylenes (mixed). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NA

Zearalenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Ziram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983

neg.

neg.

equiv.

equiv.

one

four

neg.

neg.

one

neg.

neg.

four

one

inad.

equiv.

two

two

four

two

three

neg.

neg.

four

one

neg.

neg.

neg.

three

neg.

neg.

four

two

two

inad.

two

two

inad.

inad.

three

one

three

two

one

neg.

one

four

four

neg.

one

neg.

neg.

two

one

I I

N N

E N

N N

N P

P P

N N

N N

P N

N N

N N

P P

I I

I I

E N

E N

E N

P P

I I

N P

N N

N N

P P

E P

N N

N N

N N

P P

N N

N N

P P

E E

N N

I I

N N

I N

I I

I I

P N

N N

P P

P N

N P

N N

E N

P P

P P

N N

I I

; :

N N

P N

N N

N N

N N

E N

E N

P P

N N

N N

N N

N N

N N

P P

E P

I I

N N

P P

P P

P P

P P

P P

N N

N N

P P

I I

N N

N N

N N

N P

N N

N N

P P

P P

P P

I I

P P

P P

I I

N N

P P

N P

N P

N P

N N

N N

N P

P P

P P

N N

1 P

N N

N N

P P

N E

~991

~72]

[231]

~85]

[83]

[ll q

~38]

[102]

[20]

[224]

fl14]

[209)

[2014

[201b]

[131]

[311]

[13]

[33]

[166]

[296]

[47]

[57]

[97]

[51]

[31]

[251]

[200]

~26]

~53]

[371

[~;]

[2]

[243]

[273]

f106]

~55]

[34]

[160]

[81]

[12!31

p391

[274]

[761

[58]

[71]

[30q

[228]

[327]

[235]

[238]

KEY: P—phosphate; N–negative; l—inadequate;E—equivocal; NA—notavallable.

“Indicates listing in Annual Report on Carcinogerrs.

SOURCE: Haseman, J.K. Huff, J.E. Zeiger, E.E., etal. ’’Results of 327 Chemical Carcinogenicity Studies Conducted by the National Cancef lnstituteandthe National

Toxicology Program:’ Environ. Health Perspectives (in press)
Appendix C

Acknowledgments

OTA acknowledges the following individuals and groups for their assistance in reviewing drafts or furnishing information and materials:

Lois P. Adams

Food and Drug Administration

Department of Health and Human Services

Kulbi Bakshar*

Board on Environmental Studies and Toxicology

National Academy of Sciences

Donald G, Barnes

Office of Pesticides and Toxic Substances

Environmental Protection Agency

Diane D. Beal, Ph.D

Office of Pesticides and Toxic Substances

Environmental Protection Agency

John Blodgett’

Congressional Research Service

Norman Breslow, Ph.D.

School of Public Health and Community Medicine

University of Washington

Robert Brink

Toxic Substances Control Act Interagency Testing

Committee

Gary J. Burin*

Office of Pesticides and Toxic Substances

Environmental Protection Agency

Daniel M. Byrd III, Ph. D., D. A.B.T.

Halogenated Solvents Industry Alliance

Hugh C. Cannon

Food and Drug Administration

Department of Health and Human Services

Dorothy A. Canter, Ph. D.*

National Toxicology Program

Department of Health and Human Services

Frank S. Chalmers

Occupational Safety and Health Administration

Department of Labor

Murray Cohn*

Consumer Product Safety Commission

Joseph A. Cotruvo, Ph. D.*

Office of Drinking Water

Environmental Protection Agency

Geraldine V. Cox, Ph.D.

Chemical Manufacturers Association

Jeff Davidson*

Office of Toxic Substances

Environmental Protection Agency

Philip Derfler

Food and Drug Administration

Department of Health and Human Services

Denny Dobbin

Environmental Protection Agency

David L. Dull

Office of Pesticides and Toxic Substances

Environmental Protection Agency

William Farland*

Carcinogen Assessment Group

Environmental Protection Agency

Tim Fields*

Office of Solid Waste and Emergency Response

Environmental Protection Agency

Gary Flamm

Food and Drug Administration

Department of Health and Human Services

David W. Gaylor, Ph.D.

National Center for Toxicological Research

Food and Drug Administration

Department of Health and Human Services

Clarice Gaylord

Environmental Protection Agency

Richard E. Geyer

Food and Drug Administration

Department of Health and Human Services

Vera C. Glocklin, Ph. D.*

Food and Drug Administration

Department of Health and Human Services

Michael Gough*

Environ Corp.

Murray Grant

General Accounting Office

● Participated in a workshop held on Mar. 9, 1987 to discuss the first draft of this background paper,

228
229

Martin P. Halper

Office of Toxic Substances

Environmental Protection Agency

Bryan D. Hardin, Ph.D.

National Institute for Occupational

Safety and Health

Edward D. Harrill

Consumer Product Safety Commission

Joseph K. Haseman

National Institute of Environmental Health

Sciences

Department of Health and Human Services

Michael D. Hogan, Ph.D.

National Institute of Environmental Health

Sciences

Department of Health and Human Services

John Jennings, M.D.

Pharmaceutical Manufacturers Association

James E. Huff, Ph. D.*

National Toxicology Program

Department of Health and Human Services

Boris Kachura

General Accounting Office

Robert Kellam’

Environmental Protection Agency

Thomas E. Kelly

Office of Standards and Regulations

Environmental Protection Agency

Joanne Kla

Office of Toxic Substances

Environmental Protection Agency

Edward Klein

Environmental Protection Agency

Jack Kooyoomjian’

Office of Solid Waste and Emergency Response

Environmental Protection Agency

Walter Kovalick, Jr.

Office of Emergency and Remedial Response

Environmental Protection Agency

Philip J. Landrigan, M. D., M. SC.

Department of Community Medicine

The Mount Sinai Medical Center

Dr. Richard Lemen*

National Institute for Occupational

Safety and Health

● Participated in a workshop held on Mar. 9, 1987 to discuss the first draft of this background paper.

John Martonik*

Health Standards Program

Occupational Safety and Health Administration

Carl Mazza*

Environmental Protection Agency

Ernest E. McConnell, D.V.M.

Division of Toxicology Research and Testing

Department of Health and Human Services

Tom McGarity

University of Texas Law School

J, Michael McGinnis, M.D.

Office of Disease Prevention and Health

Promotion

Department of Health and Human Services

Mortimer L. Mendelssohn

Lawrence Livermore National Laboratory

University of California

Bill Menza

Consumer Product Safety Commission

Joseph Meranda

Environmental Protection Agency

Robert J. Moolenaar

Health and Environmental Sciences

DOW Chemical Company

Barbara Ostrow

Office of Toxic Substances

Environmental Protection Agency

George H. Pauli, Ph.D.

Food and Drug Administration

Department of Health and Human Services

Frederica P. Perera, Dr., P.H.

Natural Resources Defense Council

James R. Petrie

Mine Safety and Health Administration

Department of Labor

Henry C. Pitot, M. D., Ph.D.

McArdle Laboratory for Cancer Research

Medical School

University of Wisconsin

J. Winston Porter

Office of Solid Waste and Emergency Response

Environmental Protection Agency

Peter Preuss*

Office of Health and Environment Assessment

Environmental Protection Agency
230

Tom Purcell

Office of Water Regulations and Standards

Environmental Protection Agency

Patricia A. Roberts

Office of the General Counsel

Environmental Protection Agency

Laurence S. Rosenstein*

Office of Pesticides and Toxic Substances

Environmental Protection Agency

Mark Rothstein

A. Rubin

Food and Drug Administration

Department of Health and Human Services

Mark Rushefsky

Department of Political Science & Philosophy

Southwest Missouri State University

Robert A. Scala, Ph.D.

Exxon Biomedical Sciences, Inc.

Robert J. Scheuplein

Food and Drug Administration

Department of Health and Human Services

Scott Schneider

Workers Institute for Safety and Health

Randal P. Schumacher*

Chemical Manufacturers Association

Dave Scudder

PEMD

General Accounting Office

Dan Sigelman

Human Resources and Intergovernmental Relations

Subcommittee

House of Representatives

Ellen Silbergeld*

Environmental Defense Fund

Michael Simpson

Congressional Research Service

Donald E. Stevenson*

American Industrial Health Council

William H. Sutherland

Mine Safety and Health

Department of Labor

Gary Timm

Office of Pesticides and

Administration

Toxic Substances

Environmental Protection Agency

Andrew Ulsamer

Consumer Product Safety Commission

Georgia Valaoras

Office of Policy, Planning, and Evaluation

Environmental Protection Agency

Jamie Walters

Environmental Protection Agency

Nicholas E. Weber, Ph.D.

Office of New Animal Drug Evaluation

Food and Drug Administration

James L. Weeks, SC.D.

United Mineworkers of America

Elizabeth K. Weisburger, Ph.D.

National Cancer Institute

National Institute of Health

Department of Health and Human Services

Dr. Sidney Wolfe*

Health Research Group

Mike Wright

United Steelworkers of America

● Participated in a workshop held on Mar. 9, 1987 to discuss the first draft of this background paper.
Appendix D

List of Acronyms

List of Acronyms

ACGIH —American Conference of Governmental

Industrial Hygienists

AADI —adjusted acceptable daily intake

AEC —Atomic Energy Commission

AFSCME —American Federation of State, County,

and Municipal Employees

ALARA —as low as reasonably achievable

ANPRM —Advanced Notice of Proposed Rulemaking

ASCP —American Society of Clinical Pathologists

ATSDR —Agency for Toxic Substances and Disease

Registry

BAT –best available technology

BDZ —benzodiazepine

BPT –best practicable technology

CA —chromosome aberration

CAA —Clean Air Act

CAG –Carcinogen Assessment Group (EPA)

CCERP —Committee to Coordinate Environmental

and Related Programs

CDC —Centers for Disease Control

CEC –Chemical Evaluation Committee (NTP)

CERCLA —Comprehensive Environmental Response,

Compensation, and Liability Act

CFC —chlorofluorocarbon

CHAP —Chronic Hazard Advisory Panel

CHIP —Chemical Hazard Information Profile

CHO —Chinese hamster ovary

CMA —Chemical Manufacturers Association

CMP —3-Chloro-2-methylpropene

CPSA —Consumer Product Safety Act

CPSC —Consumer Product Safety Commission

CSPI —Center for Science in the Public Interest

CSWG —Chemical Selection Working Group

CVM –Center for Veterinary Medicine (FDA)

CWA —Clean Water Act

DBCP —1,2-dibromo-3-chloropropane

DCB —1,4-Dichloro-2-butene

DDT —1,1,1-trichloro-2,2-bis(chlorophenyl)ethane

DEHP —di(2-ethylhexyl) phthalate

DEPC —diethylpyrocarbonate

DES –diethylstilbestrol

DHEW —Department of Health, Education, and

Welfare

DHHS —Department of Health and Human Services

DOE —Department of Energy

DOL —Department of Labor

DOT —Department of Transportation

EDB —ethylene dibromide

EDF

EMTD

EP

EPA

ERC

ETS

FDA

FDCA

FDF

FEPCA

FHSA

FIFRA

FRC

FYI

GAO

GRAS

HA

HEEP

HRG

HRS

HSDB

HT

HUD

IARC

ICRP

IND

IOC

IRLG

ITC

—Environmental Defense Fund

—estimated maximum tolerated dose

—extraction procedure

—Environmental Protection Agency

—Environmental Reporter Cases

—emergency temporary standards

—Food and Drug Administration

—Food, Drug, and Cosmetic Act

—fundamentally different factors

—Federal Environmental Pesticide Control

Act

—Federal Hazardous Substances Act

—Federal Insecticide, Fungicide, and

Rodenticide Act

—Federal Radiation Council

—for your information

—General Accounting Office

—generally recognized as safe

—Health Advisory

—Health and Environmental Effects Profile

—Health Research Group

—Hazardous Ranking System

—Hazardous Substance Data Bank

—Histology Technician

—Department of Housing and Urban Development

—International Agency for Research on

Cancer

—International Commission on Radiological Protection

—Investigative New Drug

—inorganic compound

—Interagency Regulatory Liaison Group

—Interagency Testing Committee

IUMRRG —Interagency Uranium Mining Radiation

Review Group

LOAEL —lowest observed adverse effect level

MBOCA —4,4-methylenebis( 2-chloroaniline)

MCL —maximum contaminant level

MCLG —maximum contaminant level goal

MDA —4,4’-methylenedianiline

MESA —Mining Enforcement and Safety Administration

MHAPPS—Modified Hazardous Air Pollutant Prioritization System

ML —mouse lymphoma

MMWR —Morbidity and Mortality Weekly Report

231
232

MOPP

MSHA

MTD

NADA

NAS

NCAB

NCAMP

NCI

NCTR

NDA

NIEHS

NIH

NIOSH

NLM

NOAEL

NOEL

NPDES

NPDWR

NPRM

NRC

NRDC

NTP

OCAW

OMB

OSHA

OSTP

OTA

—mechlorethamine [nitrogen mustard]

oncovine [vincristine], procarbazine,

prednisone

—Mine Safety and Health Administration

—maximum tolerated dose

—New Animal Drug Application

—National Academy of Sciences

–National Cancer Advisory Board (NCI)

—National Coalition Against the Misuse of

Pesticides

—National Cancer Institute

—National Center for Toxicological Research

—New Drug Application

–National Institute of Environmental Health

Sciences

—National Institutes of Health

—National Institute for Occupational Safety

and Health

—National Library of Medicine

—no observed adverse effects level

—no observed effects level

—National Pollution Discharge Elimination

System

—National Primary Drinking Water Regulations

—Notice of Proposed Rulemaking

—National Research Council

—Natural Resources Defense Council

—National Toxicology Program

—Oil Chemical and Atomic Workers International Union

—Office of Management and Budget

—Occupational Safety and Health Administration

—White House Office of Science and Technology Policy

–Congressional Office of Technology

Assessment

P, P’-DDE—1,1’-(2, dichloroethenylidine)e)

PAH —polycyclic aromatic hydrocarbon

PBBs

PCBS

PCE

PEL

PMA

PMN

POTWS

PVN

PVP

PWG

RCRA

RMCL

RPAR

RQ

SAB

SAR

SARA

SCE

SDWA

SNARL

SNUR

S o c

SOM

SR

SRI

SUR

TCDD

TCE

TDI

TDRC

TLV

TSCA

UAW

UFFI

USCG

USDA

USPHS

V o c

WLM

—polybrominated biphenyls

—polychlorinated biphenyls

—pentachloroethane

—Permissible Exposure Limit

—Pharmaceutical Manufacturers Association

—premanufacture notice

—publicly owned treatment works

—predicted value negative

—predicted value positive

—Pathology Working Group

—Resource Conservation and Recovery Act

—recommended maximum contaminant level

—rebuttable presumptions against registration

—reportable quantity

–Scientific Advisory Board (EPA)

—structure-activity relationship

—Superfund Amendments and Reauthorization Act

—sister chromatid exchange

—Safe Drinking Water Act

—suggested no adverse response level

—Significant New Use Rule

—synthetic organic chemical

—sensitivity of method

—special review

—Stanford Research Institute

—Safe Use Rule

—tretrachlorodibenzo-p-dioxin

—trichloroethylene

—toluene diisocyanate

—Toxic Design Research Committee

—threshold limit value

—Toxic Substances Control Act

—United Auto Workers

—urea-formaldehyde foam insulation

—United States Coast Guard

—United States Department of Agriculture

—United States Public Health Service

—volatile synthetic organic chemical

—working level month
References
References

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Administrative Conference of the United States,

Office of the Chairman, OSHA Rulemak”ngl%ocedures, report to the Assistant Secretary for Occupational Safety and Health, Occupational

Safety and Health Administration (Washington,

DC: Feb. 19, 1987).

Aidala, J. V., FederaZ Insecticide, Fungicide, and

Rodenticide Act: Reauthorization Issues Before

the 99th Congress, Congressional Research Service, Library of Congress, Feb. 27, 1985.

Albert, R. E., Train, R. R., and Anderson, E.,

“Rationale Developed by the Environmental Protection Agency for the Assessment of Carcinogenic Risks,”J. Nat. Cancer Inst. 58:1537-1541,

May 1977.

American Industrial Health Council, “Statement

of Donald E. Stevenson, ” presented at public

meeting on National Toxicology Program, AnnuaZ Report, Washington, DC, Apr. 21, 1987.

American Iron and Steel Institute v. Occupational Sakety and Health Adnu”nistration, Federal

Reporter, Second Series 577 (1978), p. 825.

American Textile Manufacturers Institute v.

Donovan, U.S. Reports, Second Series s77

(1981), p. 490.

Ames, B. N., “Dietary Carcinogens and Anticarcinogens,” Science 221:1256-1264, 1983.

Ames, B. N., Magaw, R., and Gold, L. S., “Ranking Possible Carcinogenic Hazards, ” Science

236:271-280, 1987.

Anderson, E. L., and U.S. Environmental Protection Agency, Carcinogen Assessment Group,

“Quantitative Approaches in Use To Assess Cancer Risk, ” Risk Analysis 3(4):77-295, 1983.

Aqua Slide n’Dive v. ConsumerProduct Safety

Commission, Federal Reporter, Second Series

569 (1978), p. 83.

Auer, C. M., “Approaches to Chemical Hazard

Assessment in the Presence of Limited Data,”

typescript, July 12, 1985.

Auer, C.M. and Francis, E. Z., Executive Summary-The PMN Process: A Discussion and

Analysis of the New Chemicals Program in the

Office of Toxic Substances, U.S. Environmental

Protection Agency, Office of Pesticides and

Toxic Substances, 1987 (forthcoming).

Bailar, J., Office on Disease Prevention and

Health Promotion, U.S. Department of Health

and Human Services, personal communication,

1987.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

Blaymore, A., “Retroactive Application of Superfund: Can Old Dogs Be Taught New Tricks?”

Boston College Environmental Affairs Law Review 12:1-50, 1978.

Brandes, R., U.S. Environmental Protection

Agency, Office of Water Enforcement and Permits, Division of Municipal Pollution Control,

personal communication, July 1986.

Brink, R. H., Executive Secretary, Toxic Substance Control Act Interagency Testing Committee, letter to OTA, Dec. 2, 1986.

Brink, R. H., Executive Secretary, Toxic Substance Control Act Interagency Testing Committee, letter to OTA, Mar. 24, 1987.

Brink, R. H., Executive Secretary, Toxic Substance Control Act Interagency Testing Committee, personal communication, 1987.

Bristol, D. W., “National Toxicology Program

Approach to Monitoring Study Performance, ”

Managing Conduct and Data Quality of Toxicology Studies, B.K. Hoover, et al. (eds. ) (Princeton, NJ: Princeton Scientific Publishing Co.,

1986).

Brown, A., “Summary of the Revised Preamble,”

presentation at the Winter Toxicology Forum,

Washington, DC, Feb. 16-18, 1987.

Burin, G., U.S. Environmental Protection Agency,

Office of Pesticide Programs, personal communications, 1986 and 1987.

Byrd, D., Halogenated Solvents Industry Alliance, personal communication, 1987.

Calkins, D. R., Dixon, R. L., Gerber, C. R., et al.,

“Identification, Characterization, and Control of

Potential Human Carcinogens: A Framework for

Federal Decision-Making,” staff paper, U.S. Office of Science and Technology Policy, Executive Office of the President, Feb. 1, 1979; printed

in Journal of the National Cancer Institute 64:

169-176, January 1980.

Camon, H. C., Associate Commissioner for Legislative Affairs, U.S. Department of Health and

Human Services, Food and Drug Administration, comments on unpublished OTA draft report, “Identifying and Regulating Carcinogens”

(1987).

Canter D., Assistant to the Director, National

Toxicology Program, U.S. Department of Health

and Human Services, letter to OTA, Jan. 27,

1987.

Canter D., Assistant to the Director, National

235

63-986 0 - 87 - 7
236

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40,

41.

Toxicology Program, U.S. Department of Health

and Human Services, personal communication,

1987.

Certified Color Manufacturers Association v.

Mathews, Federal Reporter, Second Series 543

(1976), p. 284.

Chemical & Engineering News, “Court Rules

Standards To Be Based on Health,” Chemical&

Engineering News 65(31):6, 1987.

Chemical Manufacturers Association v. NRDC,

U.S. Reports 470 (1985), p. 116.

Chemical Manufacturers Association, National

Agricultural Chemicals Association, and Pharmaceutical Manufacturers Association, “Comments on the National Toxicology Program’s

Annual Reports on Carcinogens,” presented at

public meeting on National Toxicology Program

AnnuaZ Report, Washington, DC, Apr. 21,1987.

Cherney, C. T., and Wadzinski, K. M., “State

and Federal Rules Under the Clean Water Act, ”

Nat. Resources Environ. 1:1922, 1968.

Chu, K. C., Cueto, C., and Ward, J. M., “Factors in the Evaluation of 200 National Cancer Institute Carcinogen Bioassay,” J. Toxicol. Environ. Health 8:251-280, 1981.

Cohn, M., Consumer Product Safety Commission, personal communication, 1987.

Coodley, C. F., “Risk in the 1980’s: New Perspectives on Managing Chemical Hazards,” San

Diego Law Review 21(5):1015-1044, SeptemberOctober 1984.

Cooper, R. M., “Stretching Delaney Till It Breaks,”

Regulation 9:11-17, November-December 1985.

Cotruvo, J., Director, Criteria and Standards Division, U.S. Environmental Protection Agency,

Office of Drinking Water, personal communication, 1986 and 1987.

Crump, K. S., Heel, D. G., Langely, C. H., et al,,

“Fundamental Carcinogenic Processes and Their

Implications for Low Dose Risk Assessment,”

Cancer Res. 36:2973-2979, 1976.

DeMuth, C. C., and Ginsburg, D. H., “White

House Review of Agency Rulemaking,” Harvard

Law Review 99:1075-1088, 1986.

Derfler, P., U.S. Department of Health and Human Services, Food and Drug Administration,

Office of General Counsel, comments on unpublished OTA draft report, “Identifying and Regulating Carcinogens” (1987).

Di Carlo, F. J., and Fung, V. A., “Summary of

Carcinogenicity Data Generated by the National

Cancer Institute/National Toxicology Program,”

Drug Metabol. Rev. 15(5&6):1251-1273, 1984.

Doll, R., and Pete, R., “The Causes of Cancer:

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

Quantitative Estimates of Avoidable Risks of

Cancer in the United States Today,”J. Nat. Cancer Inst. 66(6):1193-1308, June 1981, reprinted

with the same title by Oxford University Press,

1981.

Doniger, E., Senior Staff Attorney, Natural Resources Defense Council, personal communication, 1987.

Dorge, Carol L., “After ‘Voluntary’ Liability:

The EPA’s Implementation of Superfund,” l?oston College Environmental Affairs Law Review

11:443-479, 1984.

Dow Chemical v. Blum, Federal Supplement 467

(1979), p. 892.

Dow Chemical v. Consumer Product Safety

Commission, Federal Supplement 459 (1978), p.

378.

Dry Color Manufacturing Association v. Occupational Safety and Health Administration,

Federal Reporter, Second Series, 486 (1979), p.

98.

Dull, D., U.S. Environmental Protection Agency,

Office of Toxic Substances, comments on unpublished OTA draft report “Identifying and Regulating Carcinogens” (1987).

Environmental and Energy Study Institute and

the Environmental Law Institute, Statutory Deadlines in Environmental Legislation: Necessary But

Need Improvement (Washington, DC: September, 1985).

Environmental Defense Fund and Boyle, R. H.,

Malignant Neglect (New York: Vintage Books,

1980).

Environmental Defense Fund v. Environmental

Protection Agency, Federal Reporter Second Series 465 (1972), p. 528.

Environmental Defense Fund v. Environmental

Protection Agency, Federal Reporter, Second

Series 489 (1973), p, 1247.

Environmental Defense Fund v. Environmental

Protection Agency, Federal Reporter, Second

Series 510 (1975), p. 1292.

Environmental Defense Fund, v. Environmental

Protection Agency, Federal Reporter, Second

Series 548 (1978), p. 998.

Environmental Defense Fund v. Ruckelshaus,

Federal Reporter, Second Series 439 (1971), p.

584.

Environmental Defense Fund v. Train, 8 Environmental Reporter Cases (BNA) 2120 (D.D.C.

Cir. 1976), as modified sub. nom. NRDC v. Costle, 12 Environmental Reporter Cases (BNA)

1833 (D.D.C. Cir. 1979).

Environmental Monitoring Services, Inc., Tech-
237

57.

58.

59,

60.

61.

62.

63.

64.

65.

66.

67.

nical Background Document To Support Rulemaking Pursuant to CERCLA Section 102: Volume 3 (Proposed Rulemaking), report to the U.S.

Environmental Protection Agency, Contract No.

68-03-3182, December 1986.

Epstein, S. S., and Swartz, J. B., letter, Science

224:660-666, 1984.

Farland, W., Director, Carcinogen Assessment

Group, U.S. Environmental Protection, personal

communication, 1987,

Feron, V. J., Grice, H. C., Griesemer, R., et al.,

“Report 1: Basic Requirements for Long-Term

Assays for Carcinogenicity,” L.ong-T’erm and

Short-Term Screening Assays for Carcinogens:

A Critical Appraisal, R. Montesano, H. Bartsch,

and L. Tomatis (eds. ), IARC Monographs, Supplement 2 (Lyons, France: International Agency

for Research on Cancer, 1980).

Fredrickson, D. S., “Chairman’s Overview, ”

Health Research Activities of the Department of

Health, Education and Welfare: Current Efforts

and Proposed Initiatives (Washington, DC: U.S.

Department of Health, Education, and Welfare,

1979).

Funk, W., “The Exception That Proves the Rule:

FDF Variances Under the Clean Water Act,” l?oston University Journal of Environmental Affairs

13:1-60, 1985.

Gaba, J. M., “Regulation of Toxic Pollutants Under the Clean Water Act: NPDES Toxics Control Strategies, ” Journal of Air Law and Commerce 50:761-791, 1985.

Gaylor, D. W., and Kodell, R. L., “Linear Interpolation Algorithm for Low Dose Risk Assessment of Toxic Substances, ”J. of Environ. Path.

and Toxicol. 4:305-312, 1980.

Gaylor, D. W., National Center for Toxicology

Research, U.S. Department of Health and Human Services, Food and Drug Administration,

comments on unpublished OTA draft report,

“Identifying and Regulating Carcinogens” (1987).

Glocklin, V. G., “Current FDA Perspectives on

Animal Selection and Extrapolation,” paper presented at the Monsanto Environmental Health

Laboratory Toxicology Symposium, St. Louis,

MO, Oct. 27, 1985.

Glocklin, V. G., “Drug Regulation,” paper presented at Toxicology Forum, Annual Meeting,

Aspen, CO, July 28, 1980.

Glocklin, V. G., “Justification for Requiring 12-

mortth Chronic Toxicity Studies for New Drug

Substances,” paper presented at Centre for Medicines Research Workshop, London, U. K., Oct.

2, 1984.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

Glocklin, V. G., U.S. Food and Drug Administration, comments on unpublished OTA draft report, “Identifying and Regulating Carcinogens”

(1987).

Glocklin, V. G., and Temple R., U.S. Food and

Drug Administration, personal communication,

1987.

Gold, L. S., Sawyer, C. B., Magaw, R., et al., “A

Carcinogenic Potency Database of the Standardized Result of Bioassay,” Environ. Health Perspectives 58:9-319, 1984.

Graham, J. D., “The Failure of Agency-Forcing:

The Regulation of Airborne Carcinogens Under

Section 112 of the Clean Air Act,” Duke Law

Journal 19:100-150, 1985.

Gray, K., Office of General Counsel, U.S. Environmental Protection Agency, personal communication, 1986.

Griesemer, R. A., and Cueto, C., “Toward a

Classification Scheme for Degrees of Experimental

Evidence for the Carcinogenicity of Chemicals

for Animals,” Molecular and Cellular Aspects of

Carcinogen Screening Tests, R. Montesano, H.

Bartsch, and L. Tomatis (eds.) (Lyons, France:

International Agency for Research on Cancer,

1980).

Grubbs, G., Bureau Chief, Technical Support,

Permits Division, Office of Municipal Pollution

Control, U.S. Environmental Protection Agency,

personal communication, June 1986.

Grundfest, C., Pharmaceutical Manufacturers

Association, personal communication, 1986.

Gulf South Insul. v. U.S. Consumer Product

Safety Commission, Federal Reporter, Second

Series 701 (1983), p. 1137.

Hall, K., “The Control of Toxic Pollutants Under the Federal Water Pollution Control Act

Amendments of 1972,” Iowa Law Review 63:

609-648, 1978.

Hall, R., Jr., “Regulation of Problem Pollutants

Under the Federal Water Pollution Control Act:

The 1976 Consent Decree,” Proceedings of the

Second Open Forum on Management of Petroleum Refine~ Waste Water, EPA Dec. No.

600/2-78-078, March 1978.

Hall, R., Jr., “The Evolution and Implementation of EPA’s Regulatory Program To Control

the Discharge of Toxic Pollutants to the Nation’s

Waters,” Natural Resources Lawyer 10:507-529,

1977.

Halogenated Solvents Industry Alliance, “Commerits, ” statement presented at public meeting on

National Toxicology Program Annual Report,

Washington, DC, Apr. 21, 1987.
238

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93,

Harrill, E. D., Director of Congressional Relations, Consumer Product Safety Commission,

comments on unpublished OTA draft report,

“Identifying and Regulating Carcinogens” (1987).

Haseman, J. K., “Comments,” paper presented at

the Winter Toxicology Forum, Washington, DC,

Feb. 16-18, 1987.

Haseman, J. K., “Statistical Issues in the Design,

Analysis and Interpretation of Animal Carcinogenicity Studies,” Environ. Health Perspectives

58:385-392, 1984.

Haseman, J. K., Crawford, D. D., Huff, J. E., et

al., “Results From 86 Two-Year Carcinogenicity Studies Conducted by the National Toxicology Program,” J. Toxicol. Environ. Health 14:

621-639, 1984.

Haseman, J. K., Huff, J. E., Zeiger, E. E., et al.,

“Results of 327 Chemical Carcinogenicity Studies

Conducted by the National Cancer Institute and

the National Toxicology Program, ” Environ.

Health Perspectives (in press).

Hattis, D., and Smith, J. A., “What’s Wrong

With Quantitative Risk Assessment?” paper presented at the Conference on Moral Issues and

Public Policy Issues in the Use of the Method of

Quantitative Risk Assessment, Georgia State

University, Sept. 26-27, 1985.

Haworth, S., Lawlor, T., Mortelman, K., et al.,

“Salmonella Mutagenicity Test Results for 250

Chemicals,” Environ. Mutagen. 5 (Suppl. 1):3-

142, 1983.

Hercules, Inc. v. Environmental Protection

Agency, Federal Reporter, Second Series 598

(1978) pp. 91-131.

Heel, D. B., Kaplan, N. L., and Anderson, M. W.,

“Implication of Nonlinear Kinetics on Risk Assessment in Carcinogenesis, ” Sa”ence 219:1032-1037,

1983.

Hudson, E.J., “National Toxicology Program,”

Office of Program Planning and Evaluation, National Institute of Environment Health Sciences

(unpublished paper), July, 1981.

Huff, J. E., “Carcinogenesis Bioassay Results

From the National Toxicology Program,” Environ. Health Perspectives 45:185-198, 1982.

Huff J. E., Eustis, S. L., and Haseman, J. K.,

“Chemicals Causing Malignant, Malignant and

Benign, or Benign Neoplasia in 113 Recent NTP

Long-Term Carcinogenesis Studies in Rodents,”

unpublished manuscript, May 1986.

Huff J. E., McConnell, E. E., Haseman, J. K., et

al., “Carcinogenesis Studies Results of 398 Experiments on 104 Chemicals From the U.S. National Toxicology Program,” proceedings of the

Collegium Ramazzini Conference, Bologna,

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

Italy, October 1985, Annals of the New York

Academy of Sciences (in press).

Huff, J. E., Pharmacologist, Division of Toxicology Research and Testing, National Toxicology

Program, Department of Health and Human

Services, National Institute of Environmental

Health Sciences, memorandum to Dr. John Moore,

May 9, 1980.

Huff, J., Pharmacologist, Division of Toxicology Research and Testing, National Toxicology

Program, Department of Health and Human

Services, National Institute of Environmental

Health Sciences, personal communication, 1986

and 1987.

Industrial Union Department AFL-CIO v. American Petroleum Institute, U.S. Reports 448 (1980),

p. 607.

Industrial Union Depatiment AEL-CIO v. Ho&-

son, Federal Reporter, Second Series 467 (1974),

p. 467.

International Agency for Research on Cancer,

Approaches To Classifying Chemical Carcinogens According to Mechanism of Action, Technical Report No. s3/001 (Lyons, France: International Agency for Research on Cancer, 1983).

International Agency for Research on Cancer,

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Preamble, IARC

Technical Report No. 87/001 (Lyons, France:

IARC, 1987).

Jacoby, D., Counsel for Standards, U.S. Department of Labor, Office of the Solicitor, personal

communication, 1986.

Jaffe, L. L., and Nathanson, N. L., Administrative Law (Boston, MA: Little, Brown and Co.,

1968).

Juskevich J., Department of Health and Human

Services, Food and Drug Administration, Center for Veterinary Medicine, personal communication, July 27, 1987.

Kellam, R., Chief, Program Analysis and Technology Division, Office of Air and Radiation,

U.S. Environmental Protection Agency, personal

communication, July 1986.

Kelly T. E., Acting Director, Office of Standards

and Regulations, U.S. Environmental Protection

Agency, comments on unpublished OTA draft

report, “Identifying and Regulating Carcinogens”

(1987).

Keyworth, G. A., Science Advisor to the President, statement before the Subcommittee on

Commerce, Transportation, and Tourism, Committee on Energy and Commerce, U.S. House of

Representatives, Mar. 17, 1983.

Kooyoomjian, J., Office of Solid Waste and
239

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

Emergency Response, U.S. Environmental Protection Agency, personal communication, July

1986.

Kovalick W., Deputy Director, Office of Emergency and Remedial Response, U.S. Environmental Protection Agency, letter to OTA, Mar.

16, 1987.

Kover F., Chief, Chemical Screening Branch, Office of Toxic Substances, U.S. Environmental

Protection Agency, personal communication,

1987.

Lehman, A. J., Patterson, W. I., Davidow, B., et

al., “Procedures for the Appraisal of the Toxicity of Chemicals in Foods, Drugs and Cosmetics, ”

Food Drug Cosmetic Law J. 10:679-748, 1955.

Lemberg, S., Assistant General Counsel, U.S.

Consumer Product Safety Commission, personal

communication, 1986.

Lowrance, W., Of Acceptable Risk: Science and

the Determination of%fety (Los Altos, CA: William Kaufman, 1976).

Lynn, F. M., “The Interplay of Science and Values

in Assessing and Regulating Environmental Risks, ”

Sci. Technol. Human Values 11(2):40-50, Spring

1986.

Maguire, A., statement at public meeting on National Toxicology Program Annual Report,

Washington, DC, Apr. 21, 1987.

Marcus, A., “The Environmental Protection

Agency, ” in The Politics of Regulation, James

Wilson (cd. ) (New York: Basic Books, 1980).

Maronpot, R. R., Haseman, J. K., Boorman,

G. A., et al., “Liver Lesions in B6C3F1 Mice: The

National Toxicology Program, Experience and

Position,” Arch. ToxicoZ, Suppl. 10:10-26, 1987.

Marshall, E., “Carcinogenesis Without Controversy,” Science 224:1078, June 8, 1984.

Marshall, E., “Revisions in Cancer Policy,” Science 220:36-37, Apr. 1, 1983.

Martonick, J., Deputy Director, Health Standards, Occupational Safety and Health Administration, personal communication, 1986 and 1987.

Mazuzan, G. T., and Walker, J. S., ControZ of the

Atom (Berkeley, CA: University of California

Press, 1984).

McConnell E., Director Toxicology Research and

Testing Program, U.S. Department of Health

and Human Services, National Institute of Environmental Health Sciences, personal communication, 1986.

McConnell, E., Director Toxicology Research

and Testing Program, U.S. Department of Health

and Human Services, National Institute of Environmental Health Sciences, comments on unpub122.

123.

124.

125.

126.

127.

128,

129,

130.

131.

132.

133.

134.

135

lished OTA draft report, “Identifying and Reg-

ulating Carcinogens” (1987).

McGarity, T. O., “OSHA’S Generic Carcinogen

Policy: Rule Making Under Scientific and Legal

Uncertainty,” Law and Science in Collaboration,

J.D. Nyhart and M.M. Carrow (eds.) (Lexington, MA: Lexington Books, 1983).

McGaughy, R., Carcinogen Assessment Group,

U.S. Environmental Protection Agency, personal

communication, 1987.

McGinnis, J. M., Director, Office of Disease Prevention and Health Promotion, U.S. Department

of Health and Human Services, comments on unpublished OTA draft report, “Identifying and

Regulating Carcinogens” (1987).

McGuire, J., Supervisory Research Chemist,

Measurements Branch, Environmental Research

Laboratory, U.S. Environmental Protection

Agency, personal communication, 1987.

Merrill, R. A., “CPSC Regulation of Cancer Risks

in Consumer Products: 1972-1981, ” Virginia Law

Review 67:1261-1375, 1981.

Merrill, R. A., “Regulating Carcinogens in Food:

A Legislator’s Guide to the Food Safety Provisions of the Federal Food, Drug, and Cosmetic

Act,” Michigan Law Review 72:172-250, 1979.

Merrill R.A. and Schewel, “FDA Regulation of

Environmental Contaminants of Food, ” Virginia

Law Review 8:1357, 1980.

Monsanto v. Kennedy, Federal Reporters, Second Series 613 (1979), p, 947.

Moore, J., Assistant Administrator, Office of

Pesticides and Toxic Substances, U.S. Environmental Protection Agency, letter to Representative Henry Waxman, Oct. 2, 1985.

Morbidity and Mortality Weekly Report, “NIOSH

Recommendations for Occupational Safety and

Health Standards,” Morbidity and Mortality

Weekly Report 34(1 S):22S, July 19, 1985.

Morrison, A. B., “OMB Interference With Agency

Rulemaking: The Wrong Way To Write a Regulation,” Harvard Law Review 99:1059-1074,

1986.

Mortelmans, K., Haworth, S., Lawlor, T., et al.,

“Salmonella Mutagenicity Tests, II: Results From

the Testing of 270 Chemicals, ” Environ. Mutagen. 8( Suppl. 7):1-119, 1986.

National Academy of Sciences/National Research

Council, Board on Toxicology and Environmental Health Hazard, Drinking Water and

Health, vols. 1-8 (Washington, DC: NationaI

Academy Press, 1977-86).

National Academy of Sciences/National Research Council, Meat and Poultry Inspection:

63-986 0 - 87 - 8
240

136.

137,

138.

139.

140.

141.

142.

143.

144.

145,

146.

147.

The Scientific Basis of the Nation’s Program

(Washington, DC: National Academy Press,

1985).

National Academy of Sciences/National Research Council, Regulating Pesticides in Food—

The Delaney Paradox (Washington, DC: National Academy Press, 1987).

National Academy of Sciences/National Research Council, Risk Assessment in the Federal

Government: Managing the Process (Washington, DC: National Academy Press, 1983).

National Academy of Sciences/National Research Council, Toxicity Testing; Strategies To

Determine Needs and Priorities (Washington,

DC: National Academy Press, 1984).

National Association of Metal Finishers v. Environmental Protection Agency, Federal Reporter,

Second Series 719 (1983), p. 624, revised sub

nom. ChemicaJ Manufacturers Association v.

Natural Resources Defense Council, Supreme

Court Reports 105 (1985), p. 1102.

Natural Resources Defense Council v. Costle,

Environmental Reporter Cases 12 (D. D. C. Cir.,

Mar. 9, 1979).

Natural Resources Defense Council v. Environmental Protection Agency, Environmental Reporter

Cases 17 (D. D. C. Cir., July 8, 1982), p. 1721.

Natural Resources Defense Council v. Environment] protection Agency, et a]., No. 85-1150

(D. D. C. Cir., July 28, 1987).

Natural Resources Defense Council v. Gorsuch,

Environmental Reporter Cases 17 (1982), p.

2013.

Natural Resources Defense Council v. Gorsuch,

October 1982; Natural Resources Defense Council v. Ruckelshaus, August 1983; Natural Resources Defense Council v. Ruckelshaus, January 1984; Natural Resources Defense Council v.

Ruckelshaus, July 1984; Natural Resources Defense Council v. Thomas, January 198s; and

Natural Resources Defense Council v. Thomas,

April 1986, Civil Actions Nos. 73-2153, 75-0172,

75-1698, 75-1267.

Natural Resources Defense Council v. Thomas,

U.S. Court of Appeals, District of Columbia Circuit, Civil Actions 84-1387, 85-1567, brief for

petitioners (1985).

Natural Resources Defense Council v. Thomas

et al., U.S. Court of Appeals, District of Columbia Circuit, Civil Actions 84-1387,85-1567, brief

for respondents, 1985.

Natural Resources Defense Council v. Thomas,

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

No. 86 CIV 0603 (CSH), pending in S. Dist. of

N.Y.

Natural Resources Defense Council v. Train,

Environmental Reporter Cases 8(D.D.C.Cir.,

1976), p. 2120.

Nichols, A. L., and Zeckhauser, R.J., ‘The Dangers

of Caution: Conservatism in Assessment and the

Mismanagement of Risk,” Harvard University

Energy and Environmental Policy Center, John

F. Kennedy School of Government, discussion

paper series (Cambridge, MA, November 1985).

Nothstein, G. Z., The Law of Occupational

Safety and Health (New York: The Free Press,

1981).

Ohanian, E. V., and Cotruvo, J. A., “Summation

From a Regulatory Perspective,” Environmental

Health Perspectives 69:281-284, 1986.

Olson, E. D., “The Quiet Shift of Power: Office

of Management and Budget Supervision of Environmental Protection Agency Rulemaking Under Executive Order 12,291,” Virginia Journal of

Natural Resources Law 4:1-80, 1984.

Pactra Industries v. Consumer Product Safety

Commission, Federal Reporter, Second Series ss

(1977), p. 677.

Page, T., “A Framework for Unreasonable Risk

in the Toxic Substances Control Act (TSCA),”

Management of Assessed Risk for Carcinogens,

W.J. Nicholson (cd.), Annals of the New York

Academy of Sciences, vol. 363 (New York: New

York Academy of Sciences, 1981).

Perera, F. P., and Petite, C., “Formaldehyde: A

Question of Cancer Policy?” Science 216:1285-

1291, 1982.

Perera, F. P., “Quantitative Risk Assessment and

Cost-Benefit Analysis for Carcinogens at EPA:

A Critique,” J. Environ. Health Po]. (in press).

Perera, F. P., ‘The Genotoxic/Epigenetic Distinction: Relevance to Cancer Policy, ” Environ. Res.

34:175-191, 1984.

Perera F. P., Senior Science Advisor, Natural Resources Defense Council, comments on unpublished OTA draft report, “Identifying and Regulating Carcinogens” (1987).

Pete, R., and Schneiderman, M., Quantification

of Occupational Cancer, Banbury House Report

9 (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1981).

Petrie, J., U.S. Department of Labor, Mine Safety

and Health Administration, personal communication, 1986 and 1987,

Pharmaceutical Manufacturers Association,
241

“Guidelines for the Assessment of Drug and

Medical Device Safety in Animals, ” typescript,

February 1977.

162. physician’s Desk Reference (Oradell, NJ: Medical Economics Co., 1987).

163. Pitot, H. C., Fundamentals of Oncology, 3d ed.

(New York: Marcel Dekker, 1986).

164. Preuss P., Director, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, personal communication, 1986.

165. Public Citizen Health Research Group v. Auchter,

Federal Reporter, Second Series 702 (1983), p.

1150.

166. Purcell T., Office of Water Regulations and

Standards, Criteria and Standards Division, U.S.

Environmental Protection Agency, comments on

unpublished OTA draft report, “Identifying and

Regulating Carcinogens” (1987).

167. Radian Corp., Draft User’s Manual forModified

Hazardous Air Pollutant Pn”oritization System

(M.HAPPS), prepared for U.S. Environmental

Protection Agency, Office of Air Quality Planning and Standards, Pollutant Assessment Branch,

Contract No. 68-02-3889, December 1985.

168. Reagan, R., “Federal Regulation,” Executive Order No. 12291, Fed. Reg. 46(33):13193, Feb. 17,

1981.

169. Reagan, R., “Regulatory Planning Process” Executive Order No. 12498, Fed. Reg. 50:1036, Jan.

4, 1985.

170. Renwick, A. G., “Pharmacokinetics in Toxicology,” Principles and Methods of Toxicology,

A.W. Hayes (cd. ) (New York: Raven Press,

1982).

171. Rikleen, L. S., “Negotiating Superfund Settlement

Agreements,” Boston College EzzvironmentalAffairs Review 10:639-714, 1982-83.

172. Rinsky, R. A., Smith, A. B., Hornung, R., et al.,

“Benzene and Leukemia,” New EnglandJ. Med.

316:1044-1050, Apr. 23, 1987.

173. Robbins, A., Professor, Boston University School

of Public Health, statement presented at public

meeting on National Toxicology Program Annual Report, Washington, DC, Apr. 21, 1987.

174. Rodgers, W., Handbook of Environmental Law

(St. Paul, MN: West Publishing Co., 1977).

17s. Rogers, P., quoted in Occupational Health &

Safety Letter, May 22, 1987.

176. Rogers, P., statement presented at public meeting on National Toxicology Program Annual Report, Washington, DC, Apr. 21, 1987.

177. Rubin, M., Chief, Chemicals Industry Branch,

Industrial Technology Division, Office of Water,

U.S. Environmental Protection Agency, personal

communication, 1986.

178. Ruckelshaus, W. D., “Risk in a Free Society,”

Risk Anal. 4(3):157-162, 1983.

179. Rushefsky, M. E., “Assuming the Conclusions:

Risk Assessment in the Development of Cancer

Policy,” Po]. Life Sci. 4(1):31-66, August 1985.

180. Rushefsky, M. E., Making Cancer PoZicy (Albany, NY: State University of New York Press,

1986).

181. Ruttenberg, R., and Bingham, E., “A Comprehensive Occupational Carcinogen Policy as a

Framework for Regulatory Activity, ” Management of Assessed Risk for Carcinogens, W.J.

Nicholson (cd.), Annals of the New York Academy of Sciences, vol. 363 (New York: New York

Academy of Sciences, 1981).

182. Scheuplein, R., Food and Drug Administration,

personal communication, 1987.

183. Schroeder, C., “A Decade of Change in Regulating the Chemical Industry,” Law and Contemporary Problems 46(4):1, 1983.

184. Scott v. Foodand DrugAdministration, Federal

Reporter, Second Series, 728 (1984), p. 322.

185. Shackelford, W. M., and Cline, D. M., “Organic

Compounds in Water,” Environ. Sci. Technol.

20(7):652-657, 1986.

186. Silbergeld E., Environmental Defense Fund, letter to OTA, Mar. 11, 1987.

187. Society for Plastics Industn”es v. Occupational

Safety and Health Administration, Federal Reporter, Second Series s09 (197s), p. 1301.

188. Springer, J., Food and Drug Administration, persomd communication, 1987.

189. Springs Mills v. Consumer Product Safety Commission, Federal Supplement 434 (1977), p. 416.

190. Sutherland, W., Mine Safety and Health Administration, U.S. Department of Labor, personal

communication, 1986 and 1987.

191. Synthetic Organic Chemical Manufacturers Association v. Breman I, Federal Reporter, Second

Series 503 (1974), p. 1155.

192. Synthetic Organic Chemical Manufacturers Association v. Brennan II, Federal Reporter, Second

Series 506 (1974), p. 385.

193. Temple R., Director, Office of Drug Research

and Review, Center for Drugs and Biologics,

U.S. Department of Health and Human Services,

Food and Drug Administration, personal communication, Feb. 2, 1987.

194. Tennant, R. W., Margolin, B. H., Shelby, M. D.,

et al., “Prediction of Chemical Carcinogenicity

in Rodents From In Vitro Genetic Toxicity Assays,” Science 236:933-941, 1987.

195. Timm, G., Office of Toxic Substances, U.S.

Environmental Protection Agency, personal

communication, Apr. 2, 1987.
242

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206,

Todhunter, J. A., “Review of Data Available to

the Administrator Concerning Formaldehyde

and Di(2-ethylhexyl) Phthalate (DEHP), ” memo

to A.M. Gorsuch, Feb. 10, 1982.

U.S. Congress, “Joint House-Senate Summary

and Explanation, ” legislative history for Public

Law 95-622, Congressional Record 124: H13566,

Oct. 14, 1978.

U.S. Congress, General Accounting Office, Delays in EPA’s Regulation of Hazardous Air Pollutants, RCED-83-199 (Washington, DC: U.S.

Government Printing Office, Aug. 26, 1983).

U.S. Congress, General Accounting Office, Federal Efforts To Protect the Public From CancerCausing Chemicals Are Not Very Effective (Washington, DC: U.S. Government Printing Office,

1976).

U.S. Congress, General Accounting Office, Hazardous Waste: EPA Has Made Limited Progress

in Determining the Wastes To Be Regulated,

GAO/RCI!13-87-27 (Washington, DC: U.S. Government Printing Office, Dec. 1986).

U.S. Congress, General Accounting Office, IVational Toxicology Program: Efforts To Improve

Oversight of Contractors Testing Chemicals,

HRD-85-86 (Washington, DC: U.S. Government

Printing Office, 1985).

U.S. Congress, General Accounting Office, Nonag~”cultural Pesticides: Risks and Regulation

(Washington, DC: U.S. Government Printing

Office, Apr. 18, 1986).

U.S. Congress, General Accounting Office, Pesticides: EPA’s Formidable Task To Assess and

Regulate Their Risks (Washington, DC: U.S.

Government Printing Office, 1986).

U.S. Congress, House of Representatives, Committee on Agriculture, Subcommittee on Department Operations, Research, and Foreign Agriculture, Hearings on the Federal Food liradiation

Development and Control Act of 2985 (H.R.

696), Hearings, Nov. 11, 1985 (Washington, DC:

U.S. Government Printing Office, 1986).

U.S. Congress, House of Representatives, Committee on Appropriations, Subcommittee on Labor and Health Education and Welfare, Department of Labor, Health, Education and Welfare,

and Related Agencies Appropriations for 1981,

Part 4, IVationaZ Institutes of Health, Hearings,

Feb. 25, 28, 29, Mar. 3-6, 1980 (Washington,

DC: U.S. Government Printing Office, 1980).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on Oversight and Investigations, EPA’s Asbestos Regulations: Report on a Case Study on

OMB Interference in Agency Rulemaking (Wash207.

208.

209,

210.

211.

212.

213.

214.

215.

216,

217.

ington, DC: U.S. Government Printing Office,

1985).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on Oversight and Investigations, OM13 Review of CDCResearch: Impact of the Paperwork

Reduction Act (Washington, DC: U.S. Government Printing Office, 1986).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on Oversight and Investigations, Investigation of the Environmental Protection Agency,

Report on the President’s Claim of Executive

Privilege Over EPA Documents, Abuses in the

Superfund Program, and Other Matters, Committee Print 984 (Washington, DC: U.S. Government Printing Office, 1984).

U.S. Congress, House of Representatives, Committee on Government Operations, FDA’s Regulation of Zomax, H. Rpt. 98-584 (Washington,

DC: U.S. Government Printing Office, 1983).

U.S. Congress, House of Representatives, Committee on Government Operations, HHS’ Fai]-

ure To Enforce the Food, Drug, and Cosmetic

Act: The Case of Cancer-Causing Color Additives, H. Rpt. 99-151 (Washington, DC: U.S.

Government Printing Office, 1985).

U.S. Congress, House of Representatives, Committee on Government Operations, Human Food

Safety and the Regulation of Animal Drugs, H.

Rpt. 99-461 (Washington, DC: U.S. Government

Printing Office, 1985).

U.S. Congress, House of Representatives, Committee on Interstate and Foreign Commerce,

Committee Report To Accompany H.R. 14032,

H. Rpt. 94-1341 (Washington, DC: U.S. Government Printing Office, 1976).

U.S. Congress, House of Representatives, Committee on Science and Technology, Subcommittee on Investigations and Oversight, National

Toxicology Program, Hearings, July 15, 1981

(Washington, DC: U.S. Government Printing

Office, 1981).

U.S. Congress, House of Representatives, Report

To Accompany H.R. 13W2 (Safe Drinking Water

Act), H. Rpt. 93-1185 (Washington, DC: U.S.

Government Printing Office, July 10, 1974).

U.S. Congress, House of Representatives, Report

on the Safe Drinking Water Act Amendments of

1985, Rpt. N<o. 99-168.

U.S. Congress, Office of Technology Assessment, “Smoking-Related Deaths and Financial

Costs,” staff memorandum, September 1985.

U.S. Congress, Office of Technology Assessment, Assessment of Technologz”es for Determin-
243

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228,

229.

230.

ing Cancer Risks From the Environment (Washington, DC: U.S. Government Printing Office,

1981).

U.S. Congress, Office of Technology Assessment, Postmarketing Surveillance of Prescription

Drugs (Washington DC: U.S. Government Printing Office, 1982).

U.S. Congress, Office of Technology Assessment, Preventing Illness and I.njury in the Workplace (Washington, DC: U.S. Government Printing Office, 1985).

U.S. Congress, Office of Technology Assessment, Reproductive Health Hazards in the Workplace (Washington, DC: U.S. Government Printing Office, 1985).

U.S. Congress, Office of Technology Assessment, Technologies and Management Strategies

for Hazardous Waste Control (Washington, DC:

U.S. Government Printing Office, 1983).

U.S. Congress, Office of Technology Assessment, The Information Content of Premanufacture Notices (Washington, DC: U.S. Government Printing Office, 1983).

U.S. Congress, Office of Technology Assessment, Transportation of Hazardous A4aterials

(Washington, DC: U.S. Government Printing

Office, 1986).

U.S. Congress, Office of Technology Assessment, Wastes in Marine Environments (Washington, DC: U.S. Government Printing Office,

1987).

U.S. Congress, Senate, Committee on Environment and Public Works, Office of Management

and Budget Influence on Agency Actions, S. Rpt.

99-156 (Washington, DC: U.S. Government

Printing Office, 1986).

U.S. Consumer Product Safety Commission,

Commission decision not to convene a Chronic

Hazard Advisory Panel Regarding Formaldehyde

Emissions, October 1986.

U.S. Consumer Product Safety Commission,

“Children’s Pacifiers Containing Nitrosamines;

Enforcement Policy,” Fed. Reg. 48:56989, 1983.

U.S. Consumer Product Safety Commission,

“Classifying, Evaluating, and Regulating Carcinogens in Consumer Products: Interim Statement of Policy and Procedure, ” Fed. Reg. 43:58-

25665, 1978.

U.S. Consumer Product Safety Commission,

“Consumer Products Containing Benzene as an

Intentional Ingredient or as a Contaminant Under the Consumer Product Safety Act,” Proposed

Rule, Fed. Reg. 43:21838, 1978.

U.S. Consumer Product Safety Commission,

“Federal Hazardous Substance Act Regulations;

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

Part 1500-Hazardous Substances and Articles;

Administration and Enforcement Regulations, ”

Fed. Reg. 38:27017, 1973.

U.S. Consumer Product Safety Commission,

“Labeling Asbestos-Containing Household Products; Enforcement Policy, ” Fed. Reg. s1:3391o,

1986.

U.S. Department of Health and Human Services,

Committee to Coordinate Environmental and

Related Programs (CCERP), Executive Committee, “Risk Assessment and Risk Management of

Toxic Substances, A Report to the Secretary,

April 1985,” Determining Risks to Health, U.S.

Department of Health and Human Services (Dover

MA: Auburn House Publishing Co., 1986).

U.S. Department of Health and Human Services,

Determining Risks to Health (Dover, MA: Auburn House Publishing Co., 1986).

U.S. Department of Health and Human Services,

Memorandum of Understanding Between the

National Institute of Environmental Health Sciences and the National Toxicology Program, fiscal year 1986.

U.S. Department of Health and Human Services

and U.S. Environmental Protection Agency,

“Notice of the First Priority List of Hazardous

Substances That Will Be the Subject of Toxicological Profiles, ” Fed. Reg. 52:12866, 1987.

U.S. Department of Health and Human Services,

Food and Drug Administration, “General Principles for Evaluating the Safety of Compounds

Used in Food-Producing Animals, ” typescript,

JuIy 1983.

U.S. Department of Health and Human Services,

Food and Drug Administration, “Acrylonitrile

Copolymers Used To Fabricate Beverage Containers; Final Decision, ” Fed. Reg. 42:48528,

1977.

U.S. Department of Health and Human Services,

Food and Drug Administration, “Compounds

Used in Food-Producing Animals, ” Fed. Reg.

38:19226, July 19, 1973.

U.S. Department of Health and Human Services,

Food and Drug Administration, “Correction of

Listing of D&C Orange No. 17 for Use in Externally Applied Drugs and Cosmetics, ” Fed. Reg.

52:8081, Feb. 19, 1987.

U.S. Department of Health and Human Services,

Food and Drug Administration, “Correction of

Listing of D&C Red No. 19 for Use in Externally

Applied Drugs and Cosmetics, ” Fed. Reg.

52:5083, Feb. 19, 1987.

U.S. Department of Health and Human Services,

Food and Drug Administration, “D&C Green

No. 6; Listing as a Color Additive in Externally
244

Applied Drugs and Cosmetics,” Fed. Reg. 47:

14138, Apr. 2, 1982.

242. U.S. Department of Health and Human Services,

Food and Drug Administration, “Listing of D&C

Orange No. 17 for Use in Externally Applied

Drugs and Cosmetics,” Fed. Reg. 51:28331, Aug.

7, 1986.

243. U.S. Department of Health and Human Services,

Food and Drug Administration, “Listing of D&C

Red No. 19 for Use in Externally Applied Drugs

and Cosmetics, ” Fed. Reg. 51:28346, Aug. 7,

1986.

244. U.S. Department of Health and Human Services,

Food and Drug Administration, “Listing of D&C

Red No. 8 and D&C Red No. 9 for Use in Ingested Drug and Cosmetic Lip Products and Externally Applied Drugs and Cosmetics, ” Fed.

Reg. 51:43677, 43899, Dec. 5, 1986.

245. U.S. Department of Health and Human Services,

Food and Drug Administration, “Policy for Regulating Carcinogenic Chemicals in Food and

Color Additives; Advance Notice of Proposed

Rulemaking,” Fed. Reg. 47:14464, Apr. 2, 1982.

246. U.S. Department of Health and Human Services,

Food and Drug Administration, “Sponsored

Compounds in Food-Producing Animals; Proposed Rule and Notice,” Fed. Reg. 50:45530,

Oct. 31, 1985.

247. U.S. Department of Health and Human Services,

Food and Drug Administration, Advisory Committee on Protocols for Safety Evaluation, “Panel

on Carcinogenesis Report on Cancer Testing in

the Safety Evaluation of Food Additives and Pesticides, ” Toxicol. Appl. Pharmacol. 20:419-438,

1971.

248. U.S. Department of Health and Human Services,

Food and Drug Administration, Bureau of Foods,

Toxicologic Pn”nc@les for the Safety Assessment

of Direct Food Additives and Color Additives

Used in Food (Washington, DC: 1982).

249. U.S. Department of Health and Human Services,

Food and Drug Administration, comments on

unpublished OTA draft report, “Identifying and

Regulating Carcinogens” (1987).

250. U.S. Department of Health and Human Services,

National Cancer Institute, Ad Hoc Committee

on the Evaluation of Low LeveIs of Environmental Chemical Carcinogens, “Evaluation of

Environmental Carcinogens” (Report to the Surgeon General, Apr. 22, 1970), Chemicals and the

Future of Man, Hearings before Subcommittee

on Executive Reorganization and Government

Research, Committee on Government Operations, U.S. Senate, Apr. 6-7, 1971, pp. 180-190

(Washington, DC: U.S. Government Printing

Office, 1970).

251. U.S. Department of Health and Human Services,

National Cancer Institute, Guidelines for Carcinogen Bioassay in Small Rodents, NCI-CG-TR1, DHEW Pub. No. (NIH) 76-801 (Washington,

DC: U.S. Government Printing Office, February

1976).

252. U.S. Department of Health and Human Sewices,

National Institute of Occupational Safety and

Health, Division of Standards Development and

Technology Transfer, “Evaluation of Epidemiologic Studies Examining the Lung Cancer Mortality of Underground Uranium Miners, ” report

prepared for U.S. Mine Safety and Health Administration, May 9, 1985.

253. U.S. Department of Health and Human Services,

National Toxicology Program, NTP Tech. Bull.

1(3):1-2, 1980.

254. U.S. Department of Health and Human Services,

National Toxicology Program, “Announcement

of Completed Short-term Toxicology Studies on

Three Chemicals: Request for Comments,” Fed.

Reg. 51:31376, 1986.

255. U.S. Department of Health and Human Services,

National Toxicology Program, “Explanation of

Levels of Evidence of Carcinogenic Activity,”

March 1986.

256. U.S. Department of Health and Human Services,

National Toxicology Program, “General Statement of Work for the Conduct of Acute, 14-Day

Repeated Dose, 90-day Subchronic, and 2-Year

Chronic Studies in Laboratory Animals,” typescript, July 1984.

257. U.S. Department of Health and Human Services,

National Toxicology Program, Annual Plan, FY

1986, DHHS Pub. No. NTP-86-086 (Research

Triangle Park, NC, May 1986).

258. U.S. Department of Health and Human Services,

National Toxicology Program, Board of Scientific Counselors, Report of the NTP Ad Hoc

Panel on Chemical Carcinogenesis Testing and

Evaluation (Research Triangle Park, NC, Aug.

17, 1984).

259. U.S. Department of Health and Human Services,

National Toxicology Program, Board of Scientific Counselors, summary minutes, meeting of

Apr. 30 and May 1, 1985, attachment 4, p. 2.

260. U.S. Department of Health and Human Services,

National Toxicology Program, Board of Scientific Counselors, summary minutes, meeting of

Nov. 25, 1986.

261. U.S. Department of Health and Human Services,

National Toxicology Program, Chemical Evalu-
245

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

ation Committee, minutes, meeting of Sept. 16,

1986.

U.S. Department of Health and Human Services,

National Toxicology Program, First Annual 17eport on Carcinogens (Research Triangle Park,

NC, July 1980).

U.S. Department of Health and Human Services,

National Toxicology Program, Fourth Annual

Report on Carcinogens, Pub. No. NTP 85-001

(Research Triangle Park, NC, 1985).

U.S. Department of Health and Human Services,

National Toxicology Program, Review of Current DHHS, DOE, and EPA Research Related to

Toxicology, fi”scal Year 1986, Pub. No. NTP-86-

087 (Research Triangle Park, NC, 1987).

U.S. Department of Health and Human Services,

National Toxicology Program, Second Annual

Report on Carcinogens (Research Triangle Park,

NC, December 1981).

U.S. Department of Health and Human Services,

National Toxicology Program, ThirdAnnuaZReport on Carcinogens (Research Triangle Park,

NC, September 1983).

U.S. Department of Health, Education, and Welfare, Food and Drug Administration, Division

of Pharmacology, Appraisal of the Safety of

Chemicals in Foods, Drugs, and Cosmetics

(Topeka, KS: Association of Food and Drug

Officials of the United States, 1959).

U.S. Department of Health, Education, and Welfare, Public Health Service, “Establishment of a

National Toxicology Program,” Fed. Reg. 43:

53060, 1978.

U.S. Department of Labor, Mine Safety and

Health Administration, “Ionizing Radiation Standards for Underground Metal and Nonmetal Mines;

Proposed Rule,” Fed. Reg. 51:45678, 1986.

U.S. Department of Labor, Mine Safety and

Health Administration, “Recodification of Safety

and Health Standards for Metal and Nonmetal

Mines, Final Rule,” Fed. Reg. 50:4048, 1985.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Access to Employee

Exposure and Medical Records,” 29 Code of Federal Regulations 1910.20.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Final Standard on

Certain Carcinogens, “ Fed. Reg. 39:3756, 1974.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Hazard Communication,” 29 Code of Federal Regulations 1910.1200.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Identification, Classification and Regulation of Potential Occupa275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

tional Carcinogens; Conforming Deletion, ” Fed.

Reg. 46:4889, Jan. 19, 1981.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Identification, Classification and Regulation of Potential Occupational Carcinogens, ” Fed. Reg. 47:187, Jan. 5,

1982.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Identification, Classification and Regulation of Potential Occupational Carcinogens,“ Fed. Reg. 45:5002, Jan. 22,

1980.

U.S. Department of Labor, Occupational Safety

and Health Administration, “List of Substances

Which May Be Candidates for Further Scientific

Review and Possible Identification, Classification, and Regulation as Potential Occupational

Carcinogens, ” Fed. Reg. 45:53672, Aug. 12,

1980.

U.S. Department of Labor, Occupational Safety

and Health Administration, “Occupational Exposure to Coal Tar Pitch Volatiles; Modification

of Interpretation, Final Interpretation, ” F&f. Reg.

48:2764, 1983.

U.S. Environmental Protection Agency, “Additional U.S. Environmental Protection Agency

Guidance for the Health Assessment of Suspect

Carcinogens With Specific Reference to Water

Quality Criteria” (draft, June 21, 1982), PCBS

and Dioxin Cases, Hearing before Subcommittee on Oversight and Investigations, Committee

on Energy and Commerce, U.S. House of Representatives, Nov. 19, 1982, pp. 105-124 (Washington, DC: U.S. Government Printing Office,

1982).

U.S. Environmental Protection Agency, “Asbestos; Proposed Mining and Import Restrictions

and Proposed Manufacturing Importation and

Processing Prohibitions,” Fed. Reg. 51:3738, Jan.

29, 1986.

U.S. Environmental Protection Agency, “Data

Requirements for Pesticide Registration; Final

Rule,” Fed. Reg. 49:42856, Oct. 24, 1984e.

U.S. Environmental Protection Agency, “Development of Water Quality Based Permit Limitations for Toxic Pollutants; National Policy,” Fed.

Reg. 49:9017, 1984.

U.S. Environmental Protection Agency, “Formaldehyde; Determination of Significant Risk;

Advance Notice of Proposed Rulemaking,” Fed.

Reg. 49:21870-98, May 23, 1984.

U.S. Environmental Protection Agency, “Guidelines for Carcinogen Risk Assessment,” Fed. Reg.

51:33992, 1986.
246

285. U.S. Environmental Protection Agency, “Guidelines for Exposure Assessment,” Fed. Reg. 51:

34042, 1986.

286. U.S. Environmental Protection Agency, “Guidelines for Health Risk Assessment of Suspect Developmental Toxicants, ” Fed. Reg. 51:34028,

1986.

287. U.S. Environmental Protection Agency, “Guidelines for Mutagenicity Risk Assessment,” Fed.

Reg. 51:34006, 1986.

288. U.S. Environmental Protection Agency, “Hazardous Waste Management System: Identification and Listing of Hazardous Waste, Final Rule,”

Fed. Reg. 45:33084, 1980.

289. U.S. Environmental Protection Agency, “Hazardous Waste Management System: Identification and Listing of Hazardous Waste, ” Fed. Reg.

45:33084, 1980.

290. U.S. Environmental Protection Agency, “Hazardous Waste Guidelines and Regulations, ” Fed.

Reg. 43:58946, 1978.

291. U.S. Environmental Protection Agency, “Hazardous Waste Management System; Dioxin-Containing Waste,” Fed. Reg. 50:1978, 1985.

292. U.S. Environmental Protection Agency, “Health

and Safety Data Reporting; Submission of Lists

and Copies of Health and Safety Studies, ” Fed.

Reg. 51:27562, 1986.

293. U.S. Environmental Protection Agency, “Health

Risk and Economic Impact Assessments of Suspected Carcinogens: Interim Procedures and

Guidelines,” Fed. Reg. 41:402, 1976.

294. U.S. Environmental Protection Agency, “Inert

Ingredients in Pesticide Products; Policy Statement,” Fed. Reg. 52:13305, 1987.

295. U.S. Environmental Protection Agency, “Inert

Ingredients in Pesticide Products; Policy Statemerit, ” Fed. Reg. 52:13305, 1987.

296. U.S. Environmental Protection Agency, “Intent

To List Chloroform as a Hazardous Air Pollutant,” Fed. Reg. 50:39626, 1985.

297. U.S. Environmental Protection Agency, “List of

Office of Toxic Substances Documents Submitted

to the Office of Technology Assessment in Response to the Request of May 16, 1986, ” letter

to OTA.

298. U.S. Environmental Protection Agency, “National Emission Standards for Hazardous Air

Pollutants; Policy and Procedures for Identifying, Assessing, and Regulating Airborne Substances Posing a Risk of Cancer, ” Fed. Reg.

44:58642, 1979.

299. U.S. Environmental Protection Agency, “National Primary Drinking Water Regulations;

Synthetic Organic Chemicals, Inorganic Chemicals and Microorganisms, ” Fed. Reg. 50:46936,

1985.

300. U.S. Environmental Protection Agency, “National Primary Drinking Water Regulations;

Volatile Synthetic Organic Chemicals, Proposed

Rulemaking,” Fed. Reg. 49:24330, 1984.

301. U.S. Environmental Protection Agency, “National Primary Drinking Water Act Regulations;

Volatile Synthetic Organic Chemicals,” Fed. Reg.

50:46880, 1985.

302. U.S. Environmental Protection Agency, “National Primary Drinking Water Regulations;

Synthetic Organic Chemicals, Inorganic Chemicals and Microorganisms, Proposed Rulemaking,” Fed. Reg. 50:46936, 1985.

303. U.S. Environmental Protection Agency, “National Revised Primary Drinking Water Regulations, Volatile Synthetic Organic Chemicals in

Drinking Water, Advance Notice of Proposed

Rulemaking,” Fed. Reg. 47:9350, 1982.

304. U.S. Environmental Protection Agency, “National Revised Primary Drinking Water Regulations,” Fed. Reg. 48:45502, 1983.

305. U.S. Environmental Protection Agency, “National Revised Primary Drinking Water Regulations, Advanced Notice of Proposed Rulemaking,” Fed. Reg. 48:45502, 1983.

306. U.S. Environmental Protection Agency, “Notice

of the First Priority List of Hazardous Substances

That Will Be the Subject of Toxicological Profiles,” Fed. Reg. 52:12866, Apr. 17, 1987.

307. U.S. Environmental Protection Agency, ‘Notification Requirements, Reportable Quantity Adjustments,” Fed. Reg. 50:13456, 1985.

308. U.S. Environmental Protection Agency, “Proposed Comprehensive Assessment Information

Rule; Proposed Rule,” Fed. Reg. 51:35762, Oct.

7, 1986. “

309. U.S. Environmental Protection Agency, “Proposed Guidelines for Carcinogen Risk Assessment; Request for Comments, ” Fed. Reg. 49:

46294, NOV. 23, 1984.

310. U.S. Environmental Protection Agency, “Proposed Guidelines for Exposure Assessment; Request for Comments,” Fed. Reg. 49:46304, Nov.

23, 1984.

311. U.S. Environmental Protection Agency, “Proposed Guidelines for Health Risk Assessment of

Suspect Developmental Toxicants and Request

for Comments,” Fed. Reg. 49:46324, Nov. 23,

1984.

312. U.S. Environmental Protection Agency, “Proposed Guidelines for Health Risk Assessment of

Chemical Mixtures and Request for Comments;

Notice,” Fed. Reg. 50:1170, Jan. 9, 1985.
247

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326,

327.

U.S. Environmental Protection Agency, “Proposed Guidelines for Mutagenicity Risk Assessment; Request for Comments, ” Fed. Reg. 49:

46314, NOV. 23, 1984.

U.S. Environmental Protection Agency, “Reportable Quantity Adjustments, ” Fed. Reg. 52:8140,

1987.

U.S. Environmental Protection Agency, “Respondent’s Brief in Support of Proposed Findings, Conclusions and Order, In Re: Stevens Industries, Inc., et. al. [consolidated DDT hearing]”

I.F. & R. Docket Nos. 63 et seq., Apr. 5, 1972.

U.S. Environmental Protection Agency, “Superfund Programs; Reportable Quantity Adjustments,” Fed. Reg. 51:34534, 1986.

U.S. Environmental Protection Agency, “Toxic

Substances Control Act Interagency Testing

Committee (ITC)—Background,” typescript, December 1986.

U.S. Environmental Protection Agency, “Toxic

Substances Control Act Test Guidelines; Final

Rules,” Fed. Reg. 50:39252, Sept. 27, 1985.

U.S. Environmental Protection Agency, “Toxic

Substances: Glycidol and Its Derivatives; Response to the Interagency Testing Committee, “

Fed. Reg. 48:57562, 1983.

U.S. Environmental Protection Agency, “Toxic

Substances; Submission of Lists and Copies of

Health and Safety Studies on Certain Substances

Subject to the 1984 RCRA Amendments,” Fed.

Reg. 51:2890, Jan. 22, 1986.

U.S. Environmental Protection Agency, ‘lJnsubstituted Phenylenediamines, Proposed Test Rule, ”

Fed. Reg. 51:472, 1986.

U.S. Environmental Protection Agency, “Water

Pollution Control; National Primary Drinking

Water Regulations, “ Fed. Reg. 52:20672, 1987.

U.S. Environmental Protection Agency, “Water

Quality Criteria Documents; Availability,” Fed.

Reg. 45:79318, Nov. 28, 1980.

U.S. Environmental Protection Agency, Office

of Air and Radiation, “National Emission Standards for Hazardous Air Pollutants; Policy and

Procedures for Identifying, Assessing, and Regulating Airborne Substances Posing a Risk of

Cancer, ” Fed. Reg. 44:58642, 1979.

U.S. Environmental Protection Agency, Office

of Air and Radiation, “National Emission Standards for Hazardous Air Pollutants; Vinyl Chloride, ” Fed. Reg. 50:1183, Jan. 9, 1985.

U.S. Environmental Protection Agency, Office

of Drinking Water, Health Advisory [or Aldicarb (Washington, D.C. September 1985).

U.S. Environmental Protection Agency, Office

328.

329.

330.

331.

332.

333.

334.

335.

336.

337,

338.

of Emergency and Remedial Response and Office of Waste Programs Enforcement, “Guidance

on Feasibility Studies Under CERCLA, ” EPA/

540/G-85/003, June 1985.

U.S. Environmental Protection Agency, Office

of Pesticide Programs, Hazard Evaluation Division, personal communication, June 1986,

U.S. Environmental Protection Agency, Office

of Pesticides Programs, Hazard Evaluation Division, Standard Evaluation Procedure, Oncogenicity Potential: Guidance for Analysis and Evaluation of Long-Term Rodent Studies, prepared by

O.E. Paynter, EPA-540/9-85-019 (Washington,

DC, June 1985).

U.S. Environmental Protection Agency, Office

of Pesticide Programs, Hazard Evaluation Group,

personal communication, June 1986.

U.S. Environmental Protection Agency, Office

of Pesticide Programs, “Report on the Status of

Chemicals in the Special Review Program, Registration Standards Program, and Data Call-in

Program,” typescript, March 1986.

U.S. Environmental Protection Agency, Office

of Pesticides and Toxic Substances, Pesticide

Assessment Guidelines, Subdivision F, Hazard

Evaluation: Human and Domestic Animals, Series 83: Chronic and Long-term Studies, EPA540/9-82-025 (Washington, DC, October 1982).

U.S. Environmental Protection Agency, Office

of Research and Development, Environmental

Research Laboratory, Frequency of Organic

Compounds Identified in Water, EpA-600/4-76-

062, December 1976.

U.S. Environmental Protection Agency, Office

of Solid Waste and Emergency Response, The

New RCRA: A Fact Book, Environmental Protection Agency, (Washington, DC, October

1985).

U.S. Environmental Protection Agency, Office

of Toxic Substances, “Chemical Selection Process—1986, ” typescript, June 11, 1986.

U.S. Environmental Protection Agency, Office

of Toxic Substances, “CSB Existing Chemical

Assessment Tracking System: CHIP Report, ”

Mar. 19, 1987, printout.

U.S. Environmental Protection Agency, Office

of Toxic Substances, “CSB Existing Chemical

Assessment Tracking System: CHIP Report,”

Mar. 19, 1987, provided to OTA.

U.S. Environmental Protection Agency, Office

of Toxic Substances, “Procedures Governing

Testing Consent Agreements and Test Rules Under the Toxic Substances Control Act; Interim

Final Rule,” Fed. Reg. 51:23706, June 30, 1986.
248

339. U.S. Environmental Protection Agency, Office

of Toxic Substances, ‘TSCA Report to Congress

for Fiscal Year 1986,” typescript, June 1987.

340. U.S. Environmental Protection Agency, Office

of Toxic Substances, ‘TSCA Section 8(e): Overview, Outreach, and Benefits of Implementation,” typescript, May 1, 1986.

341. U.S. Environmental Protection Agency, Office

of Toxic Substances, comments on unpublished

OTA draft report, “Identifying and Regulating

Carcinogens” (1987).

342. U.S. Environmental Protection Agency, Office

of Toxic Substances, Exposure Evaluation Division, Methods for Assessing Ekposure to Chemical Substances, vol. 1: Introduction, EPA-s60/s85-001 (Washington, DC, July 1985).

343. U.S. Environmental Protection Agency, Office

of Toxic Substances, personal communication,

1986.

344. U.S. Environmental Protection Agency, Office

of Toxic Substances, “Health and Safety Data

Reporting; Submission of Lists and Copies of

Health and Safety Studies on Certain Substances,

Final Rule,” l%d. Reg. 52:16022, 1987.

345. U.S. Environmental Protection Agency, Office

of Water Regulations and Standards, “Numeric

Criteria for Toxic Pollutants in State Water

Quality Standards,” typescript, Apr. 28, 1986.

346. U.S. Environmental Protection Agency, response

to OTA request for information, July 1986.

347. U.S. Interagency Regulatory Liaison Group,

“Scientific Bases for Identification of Potential

Carcinogens and Estimation of Risks,” J. Nat.

Cancer Inst. 63(1):241-268, July 1979, and Fed.

Reg. 44:39858, July 6, 1979.

348. U.S. National Cancer Advisory Board, Subcommittee on Environmental Carcinogenesis, “General Criteria for Assessing the Evidence for Carcinogenicity of Chemical Substances, ” J. Nat.

Cancer Inst. 58:461, February 1977.

349. U.S. Office of Management and Budget, Comments on OSHA’S Proposed Rulemaking: Occupational Exposure to Formaldehyde, March

1986.

350. U.S. Office of Management and Budget, Regulatory Program of the United States Govemznent: Apr. 1, 1986-Mar. 32, 1987 (Washington,

DC: U.S. Government Printing Office, 1986).

351. U.S. Office of Science and Technology Policy,

“Chemical Carcinogens: A Review of the Science

and Its Associated Principles, February 1985,”

%/. Reg. 50:10372, Mar. 14, 1985; reprinted in

Environ. Health Perspectives 67:201, 1986.

352. U.S. Regulatory Council, “Statement on Regulation of Chemical Carcinogens; Policy and Request for Public Comments,” Fed. Reg. 44:60038-

49, Oct. 17, 1979.

3s3. Ulsamer, A. G., White, P. D., and Preuss, P. W.,

“Evaluation of Carcinogens: Perspective of the

Consumer Product Safety Commission,” Handbook of Carcinogen Testing, H.A. Milman and

E.K. Weisburger (eds. ) (Park Ridge, NJ: Noyes

Publications, 1985).

354. United States v. GAFCorp., Federal Supplement

389 (1975), p. 1379.

3SS. Wamick, H., Office of Pesticide Programs, U.S.

Environmental Protection Agency, personal

communication, July 1986.

356. Weinstein, I. B., letter, Science 219:794-796,

1983.

3s7. Weisburger, E. K., “History of the Bioassay Program of the National Cancer Institute,” Prog.

Exp. Tumor Res. 26:187-201, 1983.

358. Weisburger, J. H., and Williams, G. M., “Chemical Carcinogens, ” Toxicology: The Basic Science

of Poisons, J. Doull, C.D. Klassen, and M.O.

Amdur (eds.) 2d ed. (New York: MacMillan,

1980).

3s9. Weisburger, J. H., and Williams, G. M., “Carcinogen Testing: Current Problems and New Appreaches, ” Science 214:401, 1981.

360. Wilbourn, J., Haroun, L., Hesletine, E., et al.,

“Response of Experimental Animals to Human

Carcinogens: An Analysis Based Upon the IARC

Monographs Program,” Carcinogenesis 7:1853,

1986.

361. Wilk, A., Fuod and Drug Administration, National Toxicology Program, Chemical Evaluation Committee, comments, minutes, meeting of

Sept. 16, 1986.

362. Wines, M., “Scandals at EPA May Have Done

In Reagan’s Move To Ease Cancer Controls,”

National Journal 15(25):1264, June 18, 1983.

363. Wolfe, S., statement presented at public meeting on National Toxicology Program Annual Report, Washington, DC, Apr. 21, 1987.

364. Wolfe, S. M., “Standards for Carcinogens: Science Affronted by Politics, ” Origins of Human

Cancer, H.H. Hiatt, J.D. Watson, and J.A. Winsten (eds. ) (Cold Spring Harbor, NY: Cold Spring

Harbor Laboratory, 1977).

365. Wrem, G. C., Director of Health Standards Programs, U.S. Occupational Safety and Health

Administration, quoted in “Cracking Down on

the Causes of Cancer,” T.B. Clark, National

Journal 10:2056, Dec. 30, 1978. -
,

249

366. Young, F., Commissioner, Food and Drug Ad- 367. Zeiger, E., Tainer, B., Haworth, S., et al,, “Salministration, “Testimony before U.S. House of monella Mutagenicity Tests, AIII: Results From

Representatives Committee on Agriculture, Sub- the Testing of 255 Chemicals, ” Environ. A4utacommittee on Department Operations, Research, gen. (in press).

and Foreign Agriculture, ” November 1986.