Assessment of Technologies for

Determining Cancer Risks From the

Environment

June 1981

NTIS order #PB81-235400
Library of Congress Catalog Card Number 81-600081

For sale by the Superintendent of Documents,

U.S. Government Printing Office, Washington, D.C. 20402
Foreword

Congressional interest in cancer is long standing and continuing. Programs in basic cancer

research, and in treatment and prevention of the disease are now complemented by some two

dozen laws directed at reducing exposures to cancer-causing substances. This report examines

the technologies used to gather and analyze information about cancer in our society, as well as

the ways in which those technologies affect and are affected by the public health and environmental legislative mandates.

The report discusses the strengths and weaknesses of data sources used for determining

trends in cancer occurrence and mortality, and reviews estimates of the contribution of various

factors—behaviors and exposures—associated with cancer in this country. Evidence linking today’s cancers with past carcinogenic influences has come mainly from epidemiology, which

continues to scrutinize aspects of the American lifestyle, for possible associations with cancer.

Congressional mandates intended to shield people from new and already-present carcinogens have heightened the need for methods to identify such harmful agents before they

have an impact on human health. Laboratory testing technologies currently used to determine

the carcinogencity of substances, and technologies that may become important in the near future are discussed and evaluated, The assessment examines the use of extrapolation techniques

for estimating human carcinogenic risks from test-derived data; the advantages and disadvantages of the available extrapolation models; and the ultimate use of these techniques in setting

standards for controlling exposures under diverse legislation. The report then looks at the problems of decisionmaking in the face of the often-great uncertainties accompanying scientific findings and the proposals for regulatory reform that have grown out of concern for these issues.

In preparing the full report, OTA staff consulted with members of the advisory panel for

the study, with contractors who prepared material for the assessment, and with other

knowledgeable persons in environmental organizations, Government, industry, labor organizations, research institutions, and universities.

A draft of the final report was reviewed by the advisory panel, chaired by Dr. Norton

Nelson, the OTA Health Program Advisory Committee, chaired by Dr. Sidney S. Lee, and by

approximately 80 other individuals and groups. We are grateful for their assistance and that of

many other people who assisted and advised in the preparation of this report.

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JOHN H. GIBBONS

Director

. . . 111
Assessment of Technologies for Determining Cancer

Risks From the Environment

Advisory Panel

Norton Nelson, Panel Chairman

Department of Environmental Medicine, New York University Medical School

David Axelrod

Commissioner of Health

State of New York

Peter A. A. Berle

Berle, Butzel, Kass, and Case

Theodore L. Cairns

E. I. DuPont de Nemours & Co.,

Inc. (retired)

Paul F. Deisler, Jr.

Vice President, Health, Safety

and Environment

Shell Oil Co.

George S. Dominguez

Director of Government

Relations

CIBA-Geigy

David Doniger

Natural Resources Defense

Council

A. Myrick Freeman

Professor of Economics

Bowdoin College

Robert Harris

Environmental Defense Fund

Priscilla W. Laws

Professor of Physics

Dickinson College

Mark Lepper

Vice President for Evaluation

Rush-Presbyterian Medical

School, St Lukes Medical Center

Brian MacMahon

Chairman, Epidemiology

Department

Harvard University School of Public Health

Robert A. Neal

President

Chemical Industry Institute

of Toxicology

Vaun A. Newill

Director, Research and

Environmental Health Division

Exxon Corp.

William J. Nicholson

Department of Community

Medicine

Mt. Sinai School of Medicine

R. Talbot Pag e

California Institute of

Technology

Margaret Seminario

Department of Occupational

Safety and Health

American Federation of Labor/

Congress of Industrial

Organizations

Alice S. Whittemore

Division of Epidemiology

Stanford University School of

Medicine

Michael Wright

Safety and Health Department

United Steelworkers of America
Assessment of Technologies for Determining Cancer

Risks From the Environment

OTA Project Staff

Joyce C. Lashof, Assistant Director, OTA

Health and Life Sciences Division

H. David Banta, Health Program Manager

Michael Gough, Project Director

Robert J. Fensterheim, * Research Associate

Hellen Gelband, * Research Associate

Virginia Cwalina, Administrative Assistant

Shirley Ann Gayheart, Secretary

Nancy L. Kenney, Secretary

Martha Ingram Finney, * Editor

Other Contributing Staff

Barbara Lausche, Senior Analyst

Elizabeth Williams, Senior Analyst

Contractors

Richard Doll, Oxford University

Richard Pete, Oxford University

Michael Baram, Bracken and Baram, Boston, Mass.

Roy Albert, New York University Medical School

William Rowe, American University

Clement Associates, Inc., Washington, D.C.

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M. Datcher Joe Henson

● OTA contract personnel,
Contents

1.

2.

3.

4.

5.

6.

Summary . . . . . . . . . . . . . . . . .

Cancer Incidence and Mortality

Factors Associated With Cancer

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Methods for Determining and Identifying Carcinogens . .............113

Extrapolation From Study-Generated Data to Estimates of Human Risk .157

Approaches to Regulating Carcinogens. . . . . . . . . . . . . . . . . . . . . .. ...175

Appendixes

A. A Comparison of the National Institute’s and the

International Agency for

of Bioassay Results . . . .

B. Unreasonable Risk . . . .

Research on Cancer’s Evaluation

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

C. Abbreviations and Glossary of Terms. . . . . . . . . . . . . . . . . . . . . .. ....221

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........227

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Summary
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1. Mortality From Major Cancer Sites inthe I.Jnited States,1978, All Races . . . . . . 4

2. Summary of Cancer-Associated Environmental Factors . . . . . . . . . . . . . . . . . . . 8

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Summary

Cancer occupies center stage in American

concern about disease because of its toll in lives,

suffering, and dollars. It strikes one out of four

Americans, kills one out of five, and as the

second-leading cause of death, following heart

disease, killed over 400,000 people in the United

States in 1979. According to estimates from the

National Center for Health Statistics (NCHS),

cancer accounted for about 10 percent of the

Nation’s total cost of illness in 1977. These numbers are distressing, but the impacts of cancer

extend beyond the numbers of lives taken and

dollars spent. The human suffering it causes

touches almost everyone.

CANCER AND “ENVIRONMENT”

Studies over the last two decades yielded a

variety of statements that 60 to 90 percent of

cancer is associated with the environment and

therefore is theoretically preventable. As it was

used in those statements and is used in this

report, “environment” encompasses anything

that interacts with humans, including substances eaten, drunk, and smoked, natural and

medical radiation, workplace exposures, drugs,

aspects of sexual behavior, and substances present in the air, water, and soil. Unfortunately,

the statements were sometimes repeated with

“environment” used to mean only air, water,

and soil pollution.

Relating exposures and behaviors to cancer

occurrence is a first step in cancer prevention.

Once carcinogenic influences are identified, efforts to control them can be undertaken toward

Cancer is a collection of about 200 diseases

grouped together because of their similar

growth processes. Each cancer, regardless of the

part of the body it affects, is believed to

originate from a single “transformed” cell. A

transformed cell is unresponsive to normal controls over growth, and its progeny may grow

and multiply to produce a tumor. Studies in

human populations and in laboratory animals

have linked exposures to certain substances with

cancer. This knowledge of cancer’s origins has

led to the conclusion that preventing interactions between cancer-causing substances and

humans can reduce cancer’s toll.

CANCER MORTALITY AND INCIDENCE

the goal of reducing cancer. This study is intended to illuminate the debates about the importance of environmental factors in cancer occurrence, the laws that require actions to reduce

exposures to cancer-causing substances (carcinogens), and describes:

● what is known about the occurrence o f

cancer and death from cancer in the United

States;

. methods to identify cancer-causing substances, exposures, and behaviors;

● methods to estimate the amount of cancer

which may result from a particular behavior or exposure;

● Federal laws that provide for regulatory

control of carcinogenic exposures; and

● options for Congress.

Nationwide mortality data are used to an- doubt, the number of Americans dying from

swer questions about the number of deaths cancer has increased during the last century.

caused by cancer in the United States. Without Paradoxically, a major part of this increase re3
—

4 ● Technologies for Determining Cancer Risks From the Environment

suited from improvements in public health and

medical care. In yearn past, infectious diseases

killed large numbers of people in infancy and

during childhood. Now that improved health

care has softened the impact of those diseases,

many more people live to old ages when cancer

causes significant mortality.

Cancer deaths are not evenly distributed

among all body sites, the lung, colon, and

breast accounting for over 40 percent of the

total (see table 1). Changes in cancer rates over

time also vary by body site. For this reason,

discussion of cancer rates at particular body

sites is more revealing than discussion of overall

trends which mask changes at individual sites.

Moreover, because some cancer-causing substances act at specific’ sites, more information

about opportunities for prevention is obtained

from the analysis of particular sites.

To permit the examination of cancer rates

over time, standardization, a statistical technique, is applied to make allowances for a

changing population structure. Standardization

allows the direct comparison of single, summary statistics, e.g., the mortality rates from

lung cancer for the entire population in 1950

and 1981. In this report, mortality rates are

standardized to the age and racial structure of

the 1970 U.S. census, unless otherwise specified.

Age-specific rates are also used extensively

for examining trends. These rates measure the

proportion of people in defined age classes who

have developed or died from cancer, and are unaffected by changes in the age structure of the

population. Of greatest importance in detecting

and identifying carcinogens, changes over time

in younger age groups often presage future,

larger changes in that group of people as they

enter older age groups.

In general, cancer mortality rates are higher

among nonwhite males than among white

males. Differences between nonwhite and white

females are less pronounced. The observed

greater fluctuations in rates from year to year

for nonwhites is consistent with the conclusion

that reporting of vital statistics is poorer for

nonwhites than for whites.

Greatest concern is expressed about the increasing trends. The largest increases since 1950

are in respiratory cancers (mainly of the lung,

larynx, pharynx, trachea), which are largely ascribed to the effects of smoking. Male respiratory cancer rates began to rise about 25 years

earlier than female rates, which reflects the difference in time when the two sexes adopted

smoking. Further evidence for the importance of

smoking in lung cancer is the recent decrease in

lung cancer mortality among males younger

than 50. The percentage of males who smoke is

known to have decreased during the last 20

years, and studies have shown that smoking

cessation reduces lung cancer occurrence. AddiTable 1.– Mortality From Major Cancer Sites in the United States, 1978, All Races

Number of deaths Percentage of total

Anatomic site Male Female Total Male Female Total

All malignant neoplasms . . . . . . . . . . . . . . . . . . . . . 215,997 180,995 396,992 100% 100% 100%

Lung, trachea, and bronchus . . . . . . . . . . . . . . . . . . 71,006 24,080 95,086 32.9 13.3 24.0

Colon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20,694 23,484 44,178 9.6 13.0 11.1

Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 34,329 34,609 0.13 19.0 8.7

Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21,674 — 21,674 10.0 5.5

Pancreas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

—

11,010 9,767 20,777 5.1 5.4 5.2

Blood (leukemia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8,683 6,708 15,391 4.0 3.7 3.1

3

Uterus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — 10,872 10,872 — 6.0 2.7

Ovary, fallopian tubes, and broad ligament. . . . . . . — 10,803 10,803 — 6.0 2.7

Bladder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6,771 3,078 9,849 3.1 1.7 2.5

Brain and other parts of nervous system. . . . . . . . . 5,373 4,362 9,735 2.5 2.4 2.5

Rectum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5,002 4,089 9,091 2.3 2.3 2.3

Oral: Buccal cavity and pharynx. . . . . . . . . . . . . . . . 5,821 2,520 8,341 2.7 1.4 2.1

Kidney and other urinary organs . . . . . . . . . . . . . . . 4,809 2,916 7,725 2.2 1.6 1.9

Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5,552 2,030 7,582 2.6 1.1 1.9

Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,537 2,511 6,048 1.6 1.4 1 .5

All other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45,785 39,446 85,231 21.2 21.8 21 .5

SOURCE: Office of Technology Assessment.
Ch. l—Summary ● 5

tionally, changes in cigarette composition are

thought to contribute to a reduced risk of lung

cancer. Decreases among men now over 50 are

not expected because those populations include

a large proportion of long-time smokers who remain at high risk.

Death rates from prostate and kidney cancers

among males have risen somewhat, and mortality rates from malignant skin tumors (melanomas) have increased in white males and females.

Mortality from breast cancer, the number one

cancer killer of women, has remained relatively

constant. Overall mortality from nonrespiratory cancers (i.e., excluding most cancers generally associated with smoking) has decreased in

females and remained constant in males during

the last 30 years.

The more satisfying trends are those that are

decreasing. The most striking, among both men

and women, has been the great decrease in

stomach cancer since 1930. Although generally

ascribed to changes in diet, the reasons for the

decrease are not known with any certainty. A

decrease in uterine cancer within the last few

decades is attributed to higher living standards,

better screening tests for early cancer, and an increase in hysterectomies, which reduces the

number of women at risk.

In general, mortality data (numbers of

deaths) are considered more reliable for deciding about trends in cancer occurrence than

are data about cancer incidence (numbers of

new cases). This is largely because nationwide

mortality data have been collected on a regular

basis for almost 50 years. In contrast, incidence

data for a sample of the entire country have

been collected systematically only since 1973 by

the National Cancer Institute’s (NCI’s) Surveillance, Epidemiology, and End Results (SEER)

program. Before that, incidence data are available only for three points in time since 1937.

The lo-percent sample of the population included in the SEER areas is not representative of the

entire population. Some groups—orientals—are

overrepresented in the data collected, and some

groups—rural blacks—are underrepresented.

Incidence rates for nonwhites, at least during

the first 4 years of the SEER program, were considered too unreliable for meaningful analysis.

Incidence data are important because they

provide information not captured in mortality

data. They record each new case of cancer

whether the person dies from cancer, is cured,

or dies from other causes.

Followup studies of SEER program participants have provided information about survival

from the various types and stages of cancer. A

problem encountered in such studies was that

people who move from the registration area

after treatment are sometimes lost to further

study, making it difficult to ascertain whether

they eventually succumb to cancer or if treatment cured them. Use of the newly established

(1981) National Death Index, by which deaths

can be identified through a single query to

NCHS rather than through a request to every

State, is expected to facilitate SEER program

followup studies. If this expectation is realized,

information from the “End Results” component

of SEER should be improved.

Data collected in the SEER program (1973-

76), in combination with data from the Third

National Cancer Survey (TNCS), carried out

from 1969 through 1971, have been interpreted

as showing an increase of more than 10 percent

in cancer incidence during the last decade. The

major changes seen in the incidence data parallel

those seen in mortality data—increases in lung

cancer and decreases in stomach and uterine

cancers. However, publication of this analysis

sparked a controversy about the true nature of

incidence trends, since only 2 years earlier an

analysis of data from the three national cancer

surveys had shown an overall decrease of about

4 percent between 1947 and 1970. Some observers are concerned about the possibility that,

after at least half a century of stable or declining

rates, cancer incidence has gone up and that the

increase might result from newly introduced

chemical carcinogens. Those who dispute the

importance of the observed increase contend

that it reflects changes in the reporting of cancer

incidence between TNCS and SEER (1973

through 1976), and not real changes in cancer

incidence. As more data are collected during the

next few years, a clearer picture of incidence

trends may emerge.
6 ● Technologies for Determining Cancer Risks From the Environment

INITIATION, PROMOTION, AND SYNERGISM

Cancer causation is thought to involve at

least two steps: an early initiation step and a

later promotion effect. A single agent may cause

both events, or two or more separate agents

working in the proper sequence may be necessary. Initiation is generally thought to involve a

genetic change in the cell, but that change is not

expressed and does not result in a tumor unless a

promotion event follows it. The latent period of

most cancers—the time between exposure to an

initiator and appearance of the disease—is often

20 years or more. This long latent period is the

cause of a great deal of apprehension among

policymakers, scientists, and the general public

because new substances and living habits are

continually introduced, and today’s harmful exposures may not cause ill effects for years.

The time between exposure to a promoter,

after initiation has occurred, and the appearance of cancer, can be much shorter. “Initiated cells” may lie quiescent if they are not

“turned on” by a promoter, and cancer may

never develop if sufficient exposures to promoters do not occur. The practical importance

of this property of promoters is illustrated by

the change in cancer risk experienced by exsmokers of cigarettes. Smoking is thought to

play both an initiation and promotion role in

cancer causation. Because of smoking’s promotional properties, the risk of cancer falls off

rapidly after a smoker quits.

Synergism, another form of interaction, occurs when two or more substances potentate

each other’s effects, producing more cancers

than can be accounted for by adding the effects

of each. The multiplicative effects of cigarette

smoking and exposure to asbestos and smoking

and exposure to radiation are well-known examples of synergism.

Unfortunately, relatively little is understood

about interacting agents—either synergisms or

initiation and promotion. In particular, promoters have not received as much experimental

attention as have initiators or complete carcinogens, which both initiate and promote.

FACTORS ASSOCIATED WITH CANCER

The possibility that cancers may be prevented

by eliminating or modifying behaviors or exposures has stimulated the continued search for

factors important in cancer causation. Importantly for prevention efforts, studies of

agents that interact in causing cancer have

shown that altering exposure to a single factor

may eliminate or greatly reduce the risk of

cancer.

Evidence for the associations between various

“factors” and cancer ranges from very strong to

very weak. Regardless of the strength of the

association, the estimated magnitude of the

amount of cancer associated with factors also

varies. For instance, the strongest associations

include those between smoking tobacco and respiratory cancers, between asbestos and cancer

of the lung and other sites, and between ionizing

radiation and cancer at many sites. While each

of the three associations is strong, the percentage of cancer associated with each is different.

Smoking is associated with more than 20 percent of cancer, asbestos with between 3 and 18

percent, and natural radiation with less than I

to 3 percent.

Table 2 (pp. 8-9) presents information about

associations between several factors and cancer.

The associations between some aspects of

human biology and reproduction and a proportion of cancer, especially in women, are well-established, as is the association of a small percentage of cancer with medical drugs. The

specifics of the association between human diet

and cancer are not understood, but diet is generally considered to be associated with a large

percentage of cancer. Infection, especially viral

infection, is associated with particular tumors

that occur mainly in people in other parts of the

world, and is also thought to be associated with

some urogenital cancers in the United States.
Ch. 1—Summary ● 7

The magnitude of associations between air and

water pollution and cancer are argued and studies to examine the associations are difficult to

design and execute. The same is true of associations between consumer products and cancer.

There is no disputing that occupational exposures to asbestos and some chemicals have

caused human cancer, and table 2 presents estimates both for asbestos-caused cancer and

total occupationally associated cancer. As the

data in the table show, there is significant disagreement about how much current cancer and

cancer in the near future is to be associated with

occupational exposures.

Associating a high or low percentage of cancer with a factor does not reflect the present-day

opportunities for prevention. For instance, diet

is considered very important, but because associations with specific elements and cancer are

poorly understood, there are few practical preventive measures now available.

The opportunities for prevention of occupation-related cancers at this time are better. Identification of a cancer-causing substance in the

workplace can lead to reductions in exposure

either by regulation or through voluntary activities on the part of industry. While reducing

or eliminating occupational exposures to carcinogens might only slightly reduce the overall

cancer toll, it could have a profound effect on

the amount of cancer among workers who may

now be at risk. A reduction of only 1 percent in

cancer mortality means 4,000 fewer cancer

deaths each year, so that even small reductions

translate into relatively large numbers.

IDENTIFICATION OF CARCINOGENS

The Federal Government has centered efforts

to control cancer on reducing exposures to

chemical and physical carcinogens.

Carcinogens can be identified through epidemiology—the study of diseases and their determinants in human populations—and through

various laboratory tests. Currently 18 chemicals

and chemical processes are listed as human

carcinogens and an additional 18 listed as probable human carcinogens by the International

Agency for Research on Cancer (IARC), a

World Health Organization agency. IARC conclusions, based on reviews of the worldwide

literature, are accepted as authoritative by

government agencies and many other

organizations.

In the United States, Congress has directed

the National Toxicology Program (NTP) to produce an annual list of carcinogens, The first list,

published in 1980, was composed of the substances identified as human carcinogens by

IARC. The next publication is to be considerably expanded and will include usage and exposure data and information on the regulatory

status of over 100 chemicals either considered to

be carcinogens or regulated by the Federal Government because of carcinogenicity.

Cancer epidemiology established the associations between the 36 substances and human cancer listed by IARC as well as the carcinogenicity

of smoking, alcohol consumption, and radiation. However, epidemiology is limited as a

technique for identifying carcinogens because

cancers typically appear years or decades after

exposure. If a carcinogen were identified 20

years after its widespread use began, many people might develop cancer from it even though its

use is then immediately discontinued. Certainly,

those people who were identified in the study as

having had their cancer caused by the substance

would have been irreparably harmed. Epidemiology is complicated because people are difficult

to study; people move from place to place,

change their type of work, change their habits,

and it is hard to locate them and to estimate

their past exposures to suspect agents.

Laboratory tests, which do not depend on

human illness and death to produce data, have

been developed to identify carcinogens. Currently, the testing of suspect chemicals in

laboratory animals, generally rats and mice, is

the backbone of carcinogen identification. The

suspect chemical is administered to the animals
8 ● Technologies for Determining Cancer Risks From the Environment

Table 2.-Summary of Cancer-Associated Environmental Factorsa

Range of estimates

Factor b Sites considered in drawing the estimates associated with factor

Diet Digestive tract, breast, endometrium, ovary 35-50 percent

Associations between diet and cancer are suggested by epidemiologic and experimental laboratory studies. Significant differences in cancer rates are observed between different population groups with varying eating habits. Dietary components,

such as high-fat and low-fiber content, and nutritional habits that affect hormonal and metabolic balances are believed more

important than additives and contaminants. The magnitude of the estimates reflect observed relationships between diet and

prominent cancer sites, e.g., breast and colon.

Tobacco Upper respiratory tract, bladder, esophagus, kidney, pancreas 22-30 percent

Tobacco is associated with cancer at many anatomical sites, principally the lung. Many estimates of the proportion of overall

cancer mortality associated with tobacco smoking are firmly based on epidemiologic studies that compared cancer mortality

among individuals with varying smoking habits. Several carcinogens act synergistically with tobacco, e.g., asbestos, alcohol,

radiation.

Occupation, asbestos Upper respiratory tract, others 3-18 percent

Several occupational exposures are firmly linked to cancer occurrence, the most important of these is asbestos. Estimates for

the contribution of asbestos to current cancer deaths and cancers in the near future range from 3 percent (1.4-4.4 percent) to

an upper estimate of 13-18 percent. Most estimates Iie toward the lower end of the range. The exposures responsible for these

cancers occurred primarily in the 1940’s and 1950’s and the resultant cancers are expected to peak in the early to mid-1980’s.

Occupation, all exposures Upper respiratory tract, others 4-38 percent

Estimates of the proportion of cancer associated with all occupational exposures range from 4 percent (2-10 percent) to a

high of 23-38 percent. The higher estimates are from a paper that estimated that asbestos is associated with 13-18 percent of

all cancer and added to that estimates of cancer associated with five other occupational exposures. Almost all other

estimates are near the lower end of the range.

Alcohol Upper digestive tract, larynx, liver 3-5 percent

Alcohol consumption is associated with cancer in the upper digestive tract and in the liver. The digestive tract cancers occur

more frequently in smokers than nonsmokers, and therefore many of these cancers could be prevented if either tobacco or

alcohol were discontinued. The majority of reliable estimates are based on apportioning a percentage of the cancers at the

alcohol-related sites to alcohol, and the numerical estimates are very similar.

Infection Uterine cervix, prostate, and other sites 1-15 percent

Epidemiologic data strongly suggest an association between a virus and cervical cancer, and cancer at that site accounts for

the lower numerical estimate. The higher estimate is much more tentative and associates all urogenital cancers in both sexes

with infections of venereal origin. Some other cancers which occur commonly in other parts of the world are strongly

associated with viral infection. They are rare in the United States.

Sexual development,

reproductive patterns, and

sexual practices Breast, endometrium, ovary, cervix, testis 1-13 percenfc

All of the hormonally related cancers in women, breast, endometrial, and ovarian are believed associated with sexual development and reproductive patients. The important characteristics are: 1) age at sexual maturity; 2) age at birth of first child; 3) age

at menopause. The higher numerical estimate includes the large number of breast cancers. Testicular cancers are associated

with developmental and hormonal abnormalities.

Pollution Lung, b/adder, rectum Less than 5 percent

Air pollution: Several epidemiologic studies of the effects of air pollution demonstrate an increased risk of lung cancer in

heavily polluted areas, but these conclusions are weakened because smoking and occupational exposures were not always

taken into account. The most important carcinogens are believed to be combustion products of fossil fuels. There is continued concern that chlorofluorocarbons introduced into the atmosphere may deplete the ozone layer. This would result in

more ultraviolet light reaching the surface of the Earth and increase the number of cases of skin cancer.

Drinking water pollution: Many carcinogenic chemicals have been identified in drinking water but the extent to which past and

present levels contribute to the overall cancer rate is uncertain. Several descriptive epidemiologic studies have suggested an

association with an increased risk of cancer but the studies are plagued by confounding variables. A soon to be released NCI

epidemiologic study is expected to provide more definitive evidence regarding the association between quality of drinking

water and bladder cancer.

Medical drugs and radiation Breast, endometrium, ovary, thyroid, bone, lung, blood (leukemia) 1-4 percent

Drugs known to be carcinogenic are used in the treatment of diseases, including some cancers. In addition, hormonal therapies, particularly the estrogens, are firmly linked to an increased cancer risk. Medical radiation exposures are known to have

caused cancer and while dosage levels can be estimated, the level of risk from present day exposures is uncertain.
Ch. l—Summary ● 9

Table 2.—Summary of Cancer-Associated Environmental Factorsa—Continued

Range of estimates

Factor b

Sites considered in drawing the estimates associated with factor

Natural radiation Skin, breast, thyroid, lung, bone, blood (leukemia) Less than 7-3 percent

There is no doubt that natural radiation, consisting of ionizing radiation from cosmic rays and radioactive materials, can cause

cancer. While disagreements persist regarding the amount of risk associated with low-level ionizing radiation, the estimates

generally agree within one order of magnitude. Ultraviolet radiation from the Sun is believed responsible for most of the

400,000 nonmelanoma skin cancers. These tumors are not usually included in quantitative estimates of cancer rates because

they are poorly recorded and generally curable. They are not included here.

Consumer products Possibly all sites Less than 1-2 percent

Substances known to be carcinogenic are present in consumer products at usually very low levels. The extent to which they

contribute to the overall cancer rate is uncertain.

Unknown associations All sites (?)

Many substances have not been tested for carcinogenicity and associations between some of those substances and cancer

may exist. Furthermore, substances newly introduced into the environment may have an impact in the future. In particular,

there is concern that point sources of pollutants, such as dumps, may be contributing to cancer. Because the associations are

unknown, the estimate is uncertain but it is certainly not zero. Additionally, stress, which may be manifested by overeating,

smoking, or in other ways, probably plays a role in cancer causation.

aManY cancers may be associated with more than one factor, Factors are not mutually excluswe, and the total, If al I associations were known, would add to much more

than 100 percent

bEstlmates are Ilsted under the factors that most closely approx,rnate the description published With them The estimates are detailed and their sources referenced In

ch. 3 CRange of single estimate

SOURCE” Off Ice of Technology Assessment

either in their food, water, air, or (less frequently) by force feeding, skin painting, or injection.

As the animals die, or when the survivors are

killed at the end of the exposure period (which is

generally the lifespan of the animal), a pathologist examines them for tumors. The number of

tumors in the exposed animals is then compared

with the number in a group of “control” animals. The controls are treated exactly as the experimentals except that they are not exposed to

the chemical under test. The finding of a significant excess of tumors in the exposed animals

compared with the number found in controls in

a well-designed, well-executed animal test for

carcinogenicity leads to a conclusion that the

chemical is a carcinogen in that species.

IARC has reviewed the literature concerning

362 substances which have been tested in animals and considers the data “sufficient” to conclude that 121 are carcinogens. For about 100

others, there was “limited” evidence of carcinogenicity, indicating that further information is

desirable, but that the available evidence produces a strong warning about carcinogenicity.

Data were “insufficient” to make decisions

about the carcinogenicity of the remaining substances. The IARC review program is active and

 continuing and updates it findings periodically.

The reliability of animal tests, bioassays, depends on their design and execution. NCI published guidelines for bioassays in 1976. Bioassays now cost between $400,000 and $1 million and require up to 5 years to complete.

Clearly such expensive tools should be used

only to test highly suspect chemicals, and much

effort is devoted to selecting chemicals for

testing.

Molecular structure analysis and examination

of basic chemical and physical properties are

used to make preliminary decisions about the

likelihood of a chemical being a carcinogen and

whether or not to test it. For instance, greater

suspicion is attached to chemicals that share

common features with identified carcinogens.

Unfortunately, not all members of a structural

class behave similarly, which places limits on

this approach. In making decisions about

whether chemicals should be tested further, scientists consider other data, including any available toxicological information. These preliminary decisions may be critical, because if a decision is made not to test a substance, nothing
10 ● Technologies for Determining Cancer Risks From the Environment

more may be learned about its toxicity. The

wrong decision might result in a carcinogen entering the environment and being ignored until

it causes disease in a large number of people.

The most exciting new developments in testing are the short-term tests, which cost from a

few hundred to a few thousand dollars and require a few days to months to complete. Such

tests have been under development for about 15

years, and most depend on biologically measuring interactions between the suspect chemical

and the genetic material, deoxyribonucleic acid

(DNA). The best-known test, the “Ames test,”

measures mutagenicity (capacity to cause genetic changes) in bacteria. Other short-term tests

use micro-organisms, nonmammalian laboratory animals, and cultured human and animal

cells. Some measure mutagenicity and some the

capacity of a chemical to alter DNA metabolism

or to transform a normal cell into a cell exhibiting abnormal growth characteristics.

Many chemicals that have already been identified as carcinogens or noncarcinogens in bioassays have also been assayed in short-term

tests to measure congruence between the two

types of tests. Results from these “validation”

studies vary, but up to 90 percent of both carcinogens and noncarcinogens were correctly

classified by short-term tests. These figures are

sometimes questioned because they were derived from studies that excluded classes of

chemicals known to be difficult to classify by

the short-term tests being evaluated. However,

the International Program for the Evaluation of

Short-Term Tests for Carcinogenicity concluded that the Ames test, in combination with

other tests, correctly identified about 80 percent

of the tested carcinogens and noncarcinogens.

That study purposefully included some chemicals known to be difficult to classify by shortterm tests, and it further demonstrates the

promise of short-term tests.

Short-term tests now play an important role

in “screening” substances to aid in making decisions about whether or not to test them in animals. The role of short-term tests is expected to

increase in the future as more such tests are developed and validated. However, the eventual

replacement of animal tests by short-term tests

is probably some time away.

One factor likely to retard replacement of animal tests by short-term tests is the poor quantitative agreement between the two kinds of

tests. Qualitative agreement, as measured in

validation studies, is good—i. e., a mutagen is

very likely to be a carcinogen—but poor quantitative agreement means that a powerful mutagen may be a weak carcinogen or the other

way around. Additionally, because there is

some evidence to support the idea that the

potency of a carcinogen in animals is predictive

of its potency in humans, the poor agreement

about potency between animal and short-term

tests may inhibit wider use of the latter tests.

PROGRAMS TO IDENTIFY CARCINOGENS

Government Programs Consumer Product Safety Commission (CPSC),

The most important recent development in

governmental management of test development

and implementation is the establishment of NTP

by the Department of Health, Education, and

Welfare in 1978. The program encompasses the

short-term and bioassay testing activities of the

Department of Health and Human Services

and the Occupational Safety and Health Administration (OSHA), participate in the selection of substances to be tested by NTP. Each of

these agencies retains responsibility for development of policies and guidelines for testing and

interpretation of results under the laws that they

administer.

(DHHS) but not the testing programs that exist NTP has assumed the management of the carin other executive branch departments. Other cinogen bioassay program that was formerly

agencies with a stake in carcinogen testing, the located at NCI. This is the largest single test proEnvironmental Protection Agency (EPA), the gram, and began the testing of about 50 chemi-
Ch. I–Summary ● 1 1

cals in fiscal year 1980; the number will drop to

about 30 in fiscal year 1981 because of budgetary limitations.

Government-sponsored cancer epidemiology

is supported principally by the National Institutes of Health, with the National Institute of

Occupational Safety and Health, and other

agencies carrying out some research. Epidemiologic research is marked by flexibility in experimental design, and it has not been placed

under an umbrella organization like NTP.

Nongovernment

Many chemical,

panics have large,

and epidemiology

Programs

drug, and petroleum comactive, inhouse toxicology

units. These resources are

employed to develop information about subANALYSES OF TEST RESULTS

Results from tests are conveniently discussed

as being “positive,” “negative,” or “inconclusive.” A “positive” test is sufficient to convince

all (or most) experts that the tested substance

causes the measured effect —e. g., cancer in bioassay. Similarly, a “negative” result is one that

convinces all (or most) experts that the tested

substance does not exert the effect measured in

the test. “Inconclusive” means that no conclusion can be drawn from the test. Test results are

analyzed initially by the scientists who conduct

the tests. Their conclusions may be reviewed by

other experts later on, and such peer review is

important for the acceptance or rejection of the

conclusions.

Positive epidemiologic results show an association between an exposure or behavior and

human cancer. When they are available and

based on a valid study, they tend to dominate

any decision to be made about carcinogenicity.

When no or limited epidemiologic data are

available, bioassays which measure carcinogenicity in intact animals are the most important source of information. The last decade saw

Government organizations, Congress, executive

agencies, and the courts, as well as private sector organizations endorse bioassays and agree

that they can be used to identify potential hustances of concern to the companies and also to

supply data to Federal regulatory agencies. One

of the most modern toxicology laboratories is

that of the Chemical Industry Institute of Toxicology (CIIT). This laboratory recently completed extensive testing of formaldehyde, which

demonstrated that the chemical causes nasal

cancer in rats. CPSC and other agencies have

proposed regulations to curtail exposures to

formaldehyde based on information from CIIT

studies.

Many epidemiologic studies and much of the

development of test procedures take place in

academic institutions. Funding for these activities comes from both Federal and non-Federal sources, and these institutions have been

important in gaining knowledge and improving

techniques.

man carcinogens. For instance, IARC concluded:

. . . it is reasonable, for practical purposes, to

regard chemicals for which there is sufficient evidence of carcinogenicity . . . in animals as if

they presented a carcinogenic risk for humans.

The use of short-term test results varies depending on whether the substance being tested is

in use or new. When making decisions about

currently used chemicals, short-term test results

are used to decide whether or not to proceed to a

bioassay, and they are accorded a supporting

role in making decisions about carcinogenicity.

In industry, short-term tests play a role in

making decisions about whether or not to proceed with development of a new chemical. A

positive result, indicating that the cost of developing the chemical for market might have to include extensive and expensive toxicological testing, may be factored into a manufacturer’s decision to develop or not to develop a chemical. A

risky chemical may be dropped from consideration for further development.

A problem that bedevils decisionmaking is

the existence of both “positive” and “negative”

results from tests of the same substance. Careful

analysis of the design and execution of the “pos-
12 ● Technologies for Determining Cancer Risks From the Environment

itive” and “negative” tests sometimes resolves

the discrepancies and allows reconciliation of

the results. When the conflicting results cannot

be explained, more importance is attached to

the positive results.

It is not possible to say how many of the

55,OOO chemicals in commerce are carcinogens.

About 7,OOO have been tested in bioassay, and

10 to 16 percent were “positive. ” However, this

percentage has little meaning when discussing

all chemicals. There is a strong bias toward testing risky chemicals, as is shown by the fact that

about half of 190 chemicals tested in NCI’s bioassay program were reported to be positive. On

the other hand, many tests done years ago are

insensitive by today’s standards and that would

tend to decrease the percentage of substances

detected as carcinogens.

The IARC list of 18 human carcinogens, plus

tobacco smoke, alcohol, radiation, and the 18

probable human carcinogens, provide a minimal answer to the question of how many substances are known to cause or probably cause

human cancer. The IARC list of 121 substances

that produced “sufficient” evidence for carcinogenicity in animals expands the number of substances that must be considered as carcinogenic

hazards for humans. These two lists add up to

the “rock-bottom” number of about 160 substances. How many more carcinogens will be

identified is uncertain, and what is known about

the tested chemicals may be overshadowed by

what is unknown both about untested chemicals

and about complex human exposures and behaviors that are not amenable to laboratory

testing.

EXTRAPOLATION FROM TEST RESULTS TO ESTIMATES OF

HUMAN CANCER INCIDENCE

Extrapolation techniques are used to estimate

the probability of human cancer from studyderived data. Extrapolation can be divided into

two parts. “Biologic extrapolation” involves the

use of scaling factors to make adjustments between biologic effects in small, short-lived laboratory animals and in humans. “Numeric extrapolation” models are used to estimate the

probability of cancer at doses below those administered to animals in a test and to estimate

cancer incidence at exposure levels other than

those measured in epidemiologic studies.

Some extrapolation models assume a “threshold” dose, a nonzero dose below which exposures are “safe” and not associated with risk. Individual thresholds may exist, because not all

individuals exposed to similar levels of carcinogens develop cancer, but such differences in sensitivity may also be explained by differences in

luck rather than in biology. However, it is generally accepted that a population threshold

which would define a “risk-free” dose for a

group of people composed of diverse individuals, if it exists, cannot now be demonstrated.

Federal agencies do not accept the idea of

thresholds in making decisions about carcinogenic risks.

Numeric extrapolation models differ in the incidence of cancer that they predict from a given

exposure. Extrapolation models which assume

that incidence at low-exposure levels is directly

proportional to dose generally estimate higher

incidence. Such “linear” models are “conservative” in that, if they err, they overestimate the

amount of disease to be expected. All governmental agencies that use extrapolation employ

linear models for predicting cancer incidence.

Other models project risks that decrease more

rapidly than dose, and they are advanced as alternatives to the linear model. The choice of a

model is important because, if an acceptable

level of risk were decided on, almost any other

model would allow higher exposures than do

linear models.

Opinions differ about whether and how extrapolation methods should be used in estimating the amount of human cancer that might be

caused by exposure to a carcinogen:
Ch. l–Summary ● 1 3

●

●

●

Some individuals object to any use of

numeric extrapolation. For them, identification of a substance as a carcinogen is

enough to justify efforts to reduce or to

eliminate exposure.

Other people see extrapolation as useful to

separate more risky from less risky substances.

The most extensive use of extrapolation is

recommended by people who urge that

extrapolation methods be used to estimate

quantitatively the amount of human cancer

likely to result from exposures. Such estimates are seen as necessary by those who

wish to compare quantitatively the risks

and benefits from carcinogens.

The disagreements among the groups who

hold different opinions about use of extrapolation are vocal and current. A particular problem

in quantitative extrapolation arises from the fact

that different extrapolation models produce

estimates of cancer incidence that differ by factors of 1,000 or more at levels of human exposure. Given such uncertainty, some labor and

environmental organizations and many individuals refuse to choose one model or another

for estimating the impact of a carcinogen on

humans, and oppose the use of quantitative extrapolation. Fewer objections are raised against

choosing a model to order carcinogens on the

basis of their likelihood of causing cancer.

Regardless of which particular model is chosen,

it should produce approximately the same relative ranking as any other.

Proponents of quantitative extrapolation

argue that careful attention to the available data

aids in choosing the correct model and reduces

chances for error. Arguments about the applicability of these techniques will continue, especially because efforts to apply cost-benefit analysis

to making decisions about carcinogens will require quantitative estimates of cancer incidence.

There are now no convincing data to dictate

which extrapolation model is best for estimating

human cancer incidence, whether from epidemiologic data or animal data, or even that one

model will be consistently better than all others.

However, one particular model for estimating

human incidence from animal data (linear, no

threshold extrapolation and relating animal and

humans on the basis of total lifetime exposure

divided by body weight) has been reported to

estimate human cancer incidence within a factor

of 10 to 100 when compared to incidence measured by epidemiologic studies. While this agreement is gratifyingly good, data exist to make

these comparisons for fewer than 20 substances.

STATUTORY AND REGULATORY DEFINITIONS OF “CARCINOGEN”

Regulation of carcinogens has been marked

by repeated arguments about the amount and

kind of evidence necessary to make decisions to

regulate substances as carcinogens. Several Federal documents describe the types of tests agencies will consider and the criteria they will apply

to make such decisions. Statements of regulatory agency policy are found in EPA’s Interim

Guideline for Carcinogenic Risk Assessment,

EPA’s air carcinogen policy statement, OSHA’s

generic cancer policy, and the Regulatory Council’s policy statement, which drew heavily on

recommendations of the Interagency Regulatory

Liaison Group (IRLG). IRLG now coordinates

Federal regulatory agency discussion about

identifying and characterizing toxic substances,

including carcinogens.

All Federal agencies accept positive epidemiologic studies as strong evidence for carcinogenicity, and a positive bioassay result in a

single species as evidence that the substance is a

potential human carcinogen. All relegate shortterm tests to a supporting role. Trade associa-
14 ● Technologies for Determining Cancer Risks From the Environment

tions, such as the American Industrial Health

Council (AIHC), fault the regulatory agency

policies. AIHC insists that positive bioassays in

two different species should be required to define a carcinogen.

The importance of the dispute about whether

a positive test in only one of two test species or

positive tests in both species is necessary to

reach a conclusion about potential human carcinogenicity is illustrated by an analysis of NCI

bioassay data. Of 190 chemicals tested, 98 were

judged positive in either one or two species.

While 44 were positive in both species, 54 were

positive in either the rat or the mouse, but not

both. Although different analytical techniques

can reduce the number of discrepant results,

there is now no resolution to the arguments

raised by one positive result in a two-species

test. The agencies take the position that public

health considerations require that results from

the more sensitive animal be taken as indicating

the substance is a potential human carcinogen,

and others disagree.

An epidemiologic study that is not positive

demonstrates that no excess cancer was detected

in that study. Clearly a study that examines

large numbers of people over a long period of

time is more likely to detect carcinogenic risks

than a smaller, shorter study. In general, epidemiology cannot detect risks at the level predicted from animal tests, and agencies specify

stringent requirements under which they would

weigh negative epidemiologic data against positive animal data. Judicial decisions have supported the prominent role given to “positive”

animal tests.

AIHC urges that all epidemiologic evidence

be considered because of uncertainties in extrapolating from animals to humans, and because human response may differ from that of

test animals. Furthermore, AIHC sees epidemiologic studies as useful for putting a limit on the

amount of risk associated with a substance.

FEDERAL GOVERNMENT DECISIONMAKING

ABOUT CARCINOGENICITY

Scientists in each regulatory agency review

study designs and results to decide for their own

agency whether or not a substance is a carcinogen and, in some cases, to estimate the number

of cancers it may cause.

Suggestions have been made by the various

groups to change the process used in deciding

whether or not a substance is a potential human

carcinogen for regulatory purposes. The suggestions propose that a single panel of scientists

evaluate study results for all Government agencies. A panel, depending on the. particular proposal, might be composed of Federal scientists,

non-Federal scientists, or both. The panel would

report its finding to all regulatory agencies.

These proposals separate the “scientific” decisions about the toxicity of the substance and its

possible impact on humans from the “policy”

decision about how to reduce risks it may pose

to humans. Policy actions to be taken on the results of the scientific decision would remain the

responsibilit y of the regulatory agencies.

Proponents claim a panel would improve the

efficiency of the regulatory process. It would

make technical decisions for all the agencies,

rather than each agency making its own, Secondly, a time limit could be imposed on panel

deliberations to ensure that its work is completed quickly. Finally, under some proposals, a

regulatory agency would initiate the panel

review of data about a suspect substance, and

therefore the review could take place when it

best fits the agency schedule.

Public interest, labor, environmental organizations, and Federal regulatory agencies oppose
Ch. 1—Summary ● 1 5

these suggestions. They see the regulatory agencies as the appropriate and lawful locations for

making decisions about risk. In general, they see

a science panel as another layer of bureaucracy

that might hinder regulatory activities, and

worry that a single panel might be more sensitive to pressure from interested parties. Furthermore, they see the division between “science” and “policy” in decisions about cancer as

illusionary. They argue that such a panel might

have the power to delay decisions by imposing a

higher standard of proof that a substance is a

carcinogen than is required by law. This, they

say, would stymie preventive “precautionary”

governmental action that they view as necessary

REGULATED CARCINOGENS

Approximately 96 substances have been regulated as carcinogens or suspect carcinogens,

and an additional 49 toxic chemicals which have

been identified as carcinogens by EPA are required to be considered for regulation under the

1977 Clean Water Act Amendments. When

overlaps between the list of already regulated

substances and those required for regulation are

taken into account, there is a total of approxto protect lives and health when certainty cannot be achieved.

The number of proposals for risk-determination panels almost guarantees that the panels

will remain an issue in Federal policy about carcinogens. Establishment of such a panel would

represent a significant change in how the Federal

Government makes decisions about health risks

and would probably require specific legislation.

In November 1980, Congress provided $0.5 million to the Food and Drug Administration

(FDA) to place a contract to investigate the feasibility of a panel. The report from the study is

expected by the end of 1982.

imately 102 substances. Fifty-seven of those

substances are regulated under more than one

law. This is expected because exposures to a carcinogen may occur in air, in water, from solid

waste on land, and in the workplace so a carcinogen may be regulated under several statutes. Twenty-one of the substances that are regulated under a single law are FDA-regulated

components of food.

COLLECTION AND COORDINATION OF

EXPOSURE AND HEALTH DATA

Congress has enacted several pieces of legislation that require Federal agencies to control

carcinogenic chemicals. OSHA is responsible

for the occupational setting; CPSC, consumer

products; FDA, some food, drugs, and cosmetics; EPA, the “environment” (air, water, and

soil); and the Department of Agriculture, food.

In order to meet their responsibilities, agencies

must collect information and assess risks.

Data about exposure histories and health

status are useful in assessing associations between the environment and cancer. Both types

of information are collected by Federal agencies

but often in separate data systems in different

agencies. Because of privacy and confidentiality restrictions, these records can seldom be

brought together to “link” information pertaining to an individual. In general, these records

either cannot be made available to researchers

or can be made available only without personal

identifiers, which makes linkage impossible.

Efforts to ease these restrictions are being

pursued.

Federal, State, and local groups collect environmental data for a multitude of reasons,

and individual programs periodically review

their monitoring capabilities and directions.

However, there is no federally coordinated

focus to review the quality and quantity of data

that are collected. Thus, there is no assurance

that adequate exposure data are collected for

identifying and estimating carcinogenic risks.
16 ● Technologies for Determining Cancer Risks From the Environment

The Toxic Substances Control Act (TSCA) of

1976 was designed to strengthen the ability of

the Federal Government to accumulate information on potentially hazardous substances and to

protect the public from their risks. TSCA required establishment of new programs at EPA,

and, not unexpectedly, there have been difficulties. A 1980 General Accounting Office

(GAO) review concluded that EPA’s “disappointing” progress in implementing TSCA was

partly because of too few staff members and recruitment problems.

TSCA’s authority for acquiring information

to assess carcinogenic risks differs, depending

on whether chemicals are “new” or “existing” in

commerce. Companies must notify EPA in a

“remanufacture notice” (PMN) of their intention to manufacture or import a new substance

at least 90 days in advance. Based upon information submitted by industry, EPA then decides

if the new substance “may present an unreasonable risk” to health or the environment. If EPA

concludes such a risk may exist, it can require

additional information before allowing manufacture.

EPA has been hampered in evaluating PMNs

because more than 60 percent of the first 199

PMNs contained no toxicity data. EPA has had

to rely on molecular-structure analysis and,

when available, short-term test results to make

premanufacture decisions. EPA has twice asked

for additional information that was not included on the PMN, and each time the company

decided not to generate the data and not to manufacture. To improve the availability of data,

EPA is considering following the lead of the Organization for Economic Cooperation and Development and requiring submission of a base

set of data including short-term test results

before it will permit manufacture. However, requiring testing of chemicals simply because they

are “new” is not now possible, and TSCA would

have to be amended to permit it.

If EPA does not take regulatory action on a

PMN, the substance maybe produced and used

as desired. However, it does not mean that the

substance is safe or approved. Once production

of the chemical is initiated, it is no longer classified as new, and EPA can require testing under

the provisions for existing chemicals. EPA can

also issue a “significant new use rule” (SNUR)

for a new chemical when there is concern that

specific uses of the chemical, other than those

specified in the PMN, might pose a risk. An

SNUR requires that EPA be notified before the

substance is used in a manner covered by the

SNUR. To date, one SNUR has been proposed,

and EPA is considering SNURs on more than 40

chemicals for which PMNs were received.

One of TSCA’s first activities related to existing chemicals was the compilation of an inventory of chemical substances manufactured in

the United States. The initial inventory, published 18 months late in June 1979 and updated

in July 1980, lists about 55,000 chemicals. EPA

can, by rule, require industry testing of potentially harmful chemicals present in commerce

if the available information, while insufficient

for an evaluation of risk, supports the finding

that the chemicals “may present an unreasonable risk” or may result in substantial or significant exposure. Screening all chemicals in commerce to choose those few most needing testing

is a large task, and TSCA established the Interagency Testing Committee (ITC) to make

recommendations about which chemicals

should be tested. ITC has recommended about

50 chemicals to EPA, but EPA has been unsuccessful in meeting deadlines for ordering tests to

be done. EPA was sued by the Natural Resources Defense Council because it failed to

meet TSCA-specified deadlines, and it is now

developing test rules under a schedule that was

produced in response to a court order.

A 1980 GAO report estimated that the initiation of a rule to require testing can take as long

as 5 years, and up to 54 months is then allowed

to complete a chronic bioassay for carcinogenicity. Hence, 9 years or more may elapse

before information about a chemical’s potential

carcinogenicity is available under the testing

provisions of TSCA.

Environmental groups are critical of EPA’s

slow progress in test-rule development and argue that EPA could move more quickly. In particular, they cite EPA’s exhaustive review of the

literature about a substance as being unnecessarily thorough for test-rule development. EPA
Ch. 1—Summary ● 1 7

cites problems that it anticipates if its literature

reviews are not so complete, as well as problems

it has faced in establishing the new program, as

reasons for its slow progress. From the other

side, industry objects to some EPA procedures,

including the agency’s intention to require

testing of some chemicals as representative of

“chemical categories. ” Industry suggests that

identifying members of a category as carcinogens will falsely prejudice attitudes towards

other members of that category. EPA counters

that testing certain representative members of

categories will be more efficient than testing

chemicals on a one-by-one basis and that the

public is better served by testing the wider range

of chemicals that can be accomplished under a

category approach. EPA’s first proposed test

rule specified testing of 5 chemicals from a

category that included 11 chemicals.

LAWS THAT PROVIDE FOR THE REGULATION

OF CARCINOGENIC RISKS

Reflecting public concern about cancer, Congress has enacted laws to regulate exposures to

carcinogens in order to protect public health.

The laws were written at different times by different Congresses and are directed at controlling

exposures from different sources. Not unexpectedly, the laws differ in the amount and type

of evidence they require, and some do and some

do not require that benefits of the carcinogen be

balanced against its risks in making decisions

about regulation. “Zero-risk” laws, such as the

Delaney clause of the Food, Drug, and Cosmetic

Act, and the Resource Conservation and

Recovery Act, direct regulatory agencies to

eliminate risks without consideration of other

factors. Because the Federal Government does

not accept a threshold level for carcinogens, a

strict interpretation of these laws would require

that risk be entirely eliminated. Proponents of

these laws point to the limited benefits associated with food additives or pollutants escaping from dumps and argue for allowing no risk

from such exposures. The opponents suggest

that consumers might choose an additive in

spite of its risks and that reducing low-level

risks from dumps may cost too much.

The “technology-based” laws, such as the

Clean Water Act, direct EPA to impose specific

levels of control, considering technical and economic feasibility. The Clean Air Act and the

Occupational Safety and Health Act are also

largely technology based. In practice, regulations from these laws direct that pollutants or

exposures be controlled by installation of specified control devices.

The “balancing” laws, the Federal Insecticide,

Fungicide, and Rodenticide Act, TSCA, and the

Consumer Product Safety Act direct agencies to

consider other factors in addition to health risk

in promulgating regulations. For instance,

TSCA directs EPA to control “unreasonable

risks” and gives the agency some leeway in

deciding what to regulate and how stringently

to regulate.

An example of the complexity of the laws and

of regulations based on them is provided by the

Clean Air Act. The section of the Act providing

for the regulation of airborne toxic substances

from stationary sources was written as “zerorisk. ” However, EPA’s proposed airborne carcinogen policy concluded that such stringent

control was not always feasible because elimination of exposure to some carcinogens might

cause too much economic disruption. EPA has

proposed that it will first apply a technologybased standard for control and then, if necessary, balance risks and other factors in making a

decision about whether any residual risk is “unreasonable” and requires further regulation. The

“unreasonable-risk’ decision is analogous to

EPA requirements under TSCA. The Clean Air

Act, then, was written as zero-risk, but regulations from it are first technology based and then

balancing.
-. .— .

18 ● Technologies for Determining Cancer Risks From the Environment

Congress, reflecting; the difficulties inherent in

regulating when risks and benefits are uncertain

and difficult to quantify, delegated to the agencies the task of operationally defining certain

key balancing terms. Words in the laws, for instance, those requiring EPA to regulate “unreasonable risks” under TSCA, were purposefully

left undefined. The agencies and the courts, by

their decisions, are now defining those terms.

Some regulatory agency lawyers have been

asked about the ability of the agencies to work

within the confines of the present laws. They expressed confidence that the agencies can administer the balancing laws (such as TSCA) and

apparently appreciate the flexibility of the laws

as they are now written.

Other observers are of the opinion that

greater attention to the balancing terms in the

law would improve the regulatory processes. To

some extent, defining a balance may mean accepting a specified risk, and Congress, composed of elected representatives, is most often

seen as the body to decide on such a level. Congress already avails itself of opportunities during oversight and reauthorization hearings to

question agencies and other organizations about

difficulties in implementing the laws. Continuation of these activities may be sufficient to

satisfy Congress that the language of the laws

does or does not present a problem that can be

rectified by congressional action.

BALANCING RISKS, COSTS, AND BENEFITS IN DECISIONS

ABOUT REGULATING CARCINOGENS

Beyond the technical level of deciding whether or not a substance is a carcinogen and estimating the amount of human cancer it may

cause is any decision that requires weighing

risks against the benefits of its continued use.

The decision is complicated by equity considerations. The people who most directly bear risks

from exposures to carcinogens are not necessarily the people who most directly benefit from the

activities that produce the risk. Depending on

conditions, either the risks or the benefits may

be accorded greater quantitative importance.

REGULATORY REFORM

Concern about increasing regulatory costs

and burdens in recent years has produced a

push for changes in regulatory decisionmaking.

Charges of overregulation or untimely regulation have been leveled at many programs, including those that regulate exposures to carcinogens.

Current procedural reform proposals include:

. more emphasis on regulatory benefit-cost

analysis;

Numerous surveys show that society wants protection from health risks and is willing to pay

for it. At the same time, economic and other

considerations cause society to attempt to spend

no more than is necessary. Uncertainties attached to estimates of health risks and economic

benefits complicate regulatory decisionmaking.

Improvements in cancer risk identification and

measurement will reduce the uncertainty, but

balancing health risks against costs of control

and the benefits of the regulated substance will

remain a difficult value judgment.

●

●

●

●

more systematic regulatory review;

more flexibility in rulemaking;

appointment of additional administrative

law judges and greater involvement of the

Administrative Conference; and

providing financial assistance to public intervenors who are seen to be at a disadvantage when opposed by resources of industry or agencies.

Each of these proposals is directed at improving regulatory decisionmaking, but not all
Ch. 1–Summary ● 1 9

would have the same effect. Increased emphasis

on benefit-cost analysis will impose an additional hurdle for proposed regulations and

reduce the number and the cost of regulations.

Opponents of this proposal cite problems with

the quantification of costs and benefits and its

ignoring of equity considerations. They object

to it as another barrier against regulations that

they see as necessary to protect health and environment.

Systematic regulatory review, whether by the

President, Congress, or courts, is also designed

to reduce the number and cost of regulations.

Opponents again object to the imposition of an

additional hurdle to the promulgation of what

they see as desirable regulations. Additionally,

they see the review as stripping the agencies of

some of the authority delegated to them by Congress and putting technical decisions into organizations which lack the necessary experience

and knowledge to deal with them.

More flexibility in rulemaking would alter

agency regulatory proceedings. The first stage

of proceedings might be conducted as an informal hearing, without employing trial-type

procedures. The right of cross-examination and

use of the full adversary process would be

reserved only for those issues which warranted

further proceedings, as determined by the

presiding hearing officer. Such increased flexibility might significantly expedite the entire administrative decisionmaking process.

OPTIONS

Options for improving technologies for determining cancer risks from the environment are

divided into four groups. The first group (options 1 through 4) is concerned with gathering

information about the occurrence and distribution of cancer in the population and carcinogenic risks in the environment. The second

group (options 5 through 7) is related to testing

substances for carcinogenicity. Options 8

through 10 relate to TSCA and its implementation. The final option is concerned with possible

changes in the process used by regulatory agenAppointment of more administrative law

judges and greater involvement of the Administrative Conference in reviewing judicial performance is intended to make the current regulatory process more responsive. Systematic regulatory review by the courts might increase the

need for administrative law judges.

Public interveners from consumer, environmental, or other groups often have interest in

regulations. They are sometimes hampered in

their efforts to participate in regulatory hearings

because of lack of finances. Providing such

groups with financial assistance would allow

them to be heard. This proposal is opposed by

those who believe public financing should not

be provided to private “public interest” groups.

The regulatory reform proposals reach to the

heart of the Federal Government’s role in protecting the health and the economic interests of

the public, both as a whole, and as composed of

diverse groups, such as labor and industry. The

decision that its current activities are appropriate and sufficient or that they should be curtailed or expanded will involve profound and

basic social, political, and equity considerations. Cancer may be the focus for such debates

about health regulation. Its toll in death and suffering is large, it is widely feared, efforts to gain

knowledge of its causes often depend on measures with wide margins of error, and payoffs

from reduced exposures may be years or even

decades away. The debate will involve more

than technical issues.

cies in making technical decisions about carcinogens.

Methods for obtaining better

about the occurrence, distribution,

of cancer.

information

and outcome

These four options are discussed separately

and can be considered for implementation separately. Adoption of any or all of the options

would improve the quality and quantity of data

available to draw conclusions about the occur-
20 . Technologies for Determining Cancer Risks From the Environment

rence and distribution of cancer. This information would allow more precise estimates to

be made about the incidence of cancer and

therefore allow accurate monitoring of cancer

trends. Results from the specific studies in option 3 might clarify many questions about relationships between particular exposures and behaviors and cancer. They would be immediately

useful for prevention programs.

OPTION 1

Expand the operation of NCI’s SEER program to collect cancer incidence and survival data representative of the entire country and design programs to assess validity

of collected data.

The SEER program, which started in 1973, is

the first continuous cancer incidence reporting

program in the United States and provides an

approximation of cancer incidence and survival

rates for the country as a whole. The SEER program has been and should continue to be a useful source of identified cancer cases which greatly facilitates studies about the disease. Detailed

diagnostic information is available on each case

recorded by the SEER program, and patients,

family members, and friends can be queried to

learn more about exposures, behaviors, and occurrence of cancer.

SEER program data are collected from about

10 percent of the total population, but the

geographical regions covered by the SEER program do not closely represent the demographic

makeup of the entire country. A slightly expanded SEER program could encompass more

of the country and be constructed so as to collect data representative of the entire population.

Expanded coverage would generate data for a

more careful and detailed examination of cancer

rates over time than what is now possible. An

important component of an expanded SEER

program could be rigorous examination of the

validity of the collected data. For instance, the

accuracy of diagnoses and transfer of the diagnosis information to the SEER program data

could be monitored to reduce uncertainties

about data. Such attention to data reliability

would make conclusions drawn from the data

more convincing and accepted.

The current SEER program costs about $10

million annually out of the total NCI budget of

about $1 billion. Expanding the program would

cost more money and would also require cooperation of additional local medical organizations to establish new SEER data collection

areas. Balanced against these costs are opportunities to gather incidence and survival data

representative of the whole country and to learn

more about cancer in the U.S. population.

OPTION 2

Establish a National Cancer Registry

(NCR) to record all new cases of cancer in

the United States.

An NCR would provide the most comprehensive data possible on cancer incidence in this

country. With a national registry, cancer would

become a reportable disease, as are some infectious diseases. This data base would be useful

for trend analysis and for identifying cancer

cases for epidemiologic study. The NCR would

record the date on which cancer was diagnosed

and could be used in conjunction with the National Death Index to generate information

about survival.

An NCR would collect less detailed information on each case than is now collected by the

SEER program, but would record on the order

of ten times more cases. Establishing an NCR

would not reduce the need for the SEER program, but rather would add to the cancer incidence data base.

About 30 States presently have enacted regulations or laws requiring that cancer cases be

reported to a central authority, but most of

those States have not yet initiated programs to

implement the laws. Establishment of an NCR

which would invite States to participate might

provide incentive for States to implement their

own programs. At the Federal level, the Centers

for Disease Control, or another appropriate organization, might serve as the agency for receiving, storing, and disseminating registry data.

The establishment of a well-structured NCR

might become a seed project for a comprehensive registry for many chronic diseases of national importance. The interrelationships and
Ch. l–Summary ● 2 1

multifactorial nature of chronic diseases make

this a worthwhile step towards the goal of

understanding major public health problems.

As a new venture, NCR would require much

money and, perhaps, a long time before it became useful for truly national studies. However,

it would be immediately useful in identifying

cancer cases for study. The percentage of cases

reported to it, if the experience of other registries is an accurate indication, would increase

with time. This increase might produce an artifactual

showed

trends,

pa ted.

“cancer epidemic” as better reporting

an increase in cases regardless of actual

but such a development can be anticiOPTION 3

Encourage epidemiologic studies to answer

specific questions. Three such studies might

be:

● study of workplace-related cancers;

. study of cancer and dietary habits; and

● study of respiratory cancer.

Study of Workplace-Related Cancers. —There

is a controversy over the amount of cancer associated with occupational exposures. Many currently available study results lend themselves

to various interpretations. Additional studies

might help resolve the existing controversies

and, more importantly, might pinpoint opportunities for regulatory and voluntary reduction

in exposures. The National Institute of Occupational Safety and Health now conducts workplace carcinogenicity studies and continuing its

support is one mechanism to obtain more information.

Cohort studies identify and follow healthy

people with a common characteristic or exposure to look for associations with subsequent

cancer occurrence. Such studies could be initiated to examine the cancer risk posed by occupational exposures to chemicals now identified as carcinogens in laboratory tests or suspect for other reasons. Priority consideration

might be given to those chemicals perceived to

have a higher degree of risk, to which many

people are exposed, and for which means of

control exist.

Study of cancer incidence and mortality at

body sites known or thought to be associated

with occupational exposures could be examined

in case-control studies, which compare exposures and behavioral histories of people afflicted

with cancer (cases) with those of unafflicted

persons (controls). Lung cancer is the most

common occupationally related cancer. Other

types, including nasopharyngeal carcinoma,

melanoma, bladder and brain cancers are

worthy of study, because of past associations

with occupational factors, but no site is free of

suspected occupational associations.

The availability of exposure data is a particularly acute problem to be addressed in designing any occupational study. Monitoring in

the workplace is now required only for a few

chemicals already regulated by OSHA, and although some companies monitor levels of suspect substances, no information is routinely

available for many other chemicals. However,

OSHA now requires that a company retain ail

exposure records that it collects and any collected data can be made available for study. For

cohort studies, it may be necessary to initiate

and continue monitoring for many years before

results are obtainable. Results from such studies

are considered very powerful.

Studies of Cancer and Dietary Habits.—Diet

is generally considered an important factor in

cancer causation, but few specifics are known.

Long-term cohort studies could be designed to

investigate relationships between dietary variables and cancer. For example, different ethnic

populations with distinct eating habits could be

followed and their cancer incidence ascertained

over the years. Such studies are expensive and

time-consuming, but they may provide otherwise unobtainable information about risk factors and protective agents in food.

Large-scale case-control studies also could

investigate hypotheses relating diet and particular cancer sites. Congress mandated one such

study to investigate whether or not nonnutritive

sweeteners cause human bladder cancer. The

study involved questioning of 3,000 persons

with bladder cancer (cases) and 6,000 others

without bladder cancer (controls). The study
22 ● Technologies for Determining Cancer Risks From the Environment

showed “that past artificial sweetener use has

had a minimal effect, if any, on bladder cancer

rates.” The same study was used to investigate

possible links between water quality and bladder cancer. Results from that part of the study

are expected to be published in 1981. Case-control studies might also associate particular diets

with reduced cancer risks which would provide

information immediately useful for prevention.

The long latent period between exposures

associated with cancer and manifestation of the

disease makes associations between them difficult to determine. One possible way to improve this situation, especially for diet-related

cancer research, might be to establish a Biological Samples Bank. Such a bank would store

samples of urine, hair, blood, feces, and perhaps tissues, as well as answers to questions

about diet, recreation, and work from as many

as a quarter-million people. An additional activity of the bank would be to obtain a copy of

the death certificate for each person represented

in the bank. The certificate would be included in

the individual record. The data could be stored

on microfiche, and the biological samples would

be stored under the best possible conditions. No

additional processing of the sample and data

would be undertaken by the bank, but they

would be held until requested by researchers. A

researcher investigating a particular illness or

cause of death could request questionnaire data

and biological samples collected from people

who became sick with or who died from that

disease. The same information and samples obtained from people who were not afflicted

would provide control data.

The Biological Samples Bank would have

some of the advantages of large-scale cohort

studies but at lower cost. Money would not be

expended in following individuals for long

periods of time or in carrying out analyses that

would not be utilized, and a charge levied for

each sample provided to a researcher would

offset some of the costs of the program. The

bank would allow both Government and nonGovernment scientists to test hypotheses in a

wide range of areas. The program would be far

larger than anything like it ever attempted, and

its management would have to be carefully

planned or access to samples might be So cumbersome that the bank would be unusable.

Studies of Respiratory Cancer.—Cancers of

the respiratory tract, breast, and colon account

for the majority of cancer cases and deaths.

Studies which could relate exposures and behaviors with cancer at these sites might produce

important information for prevention. In particular, a large case-control study of respiratory

cancer would answer several important questions. A sufficiently large study should include

on the order of 10,000 cases, about one-tenth of

1 year’s total respiratory cancers, and ideally,

twice that number of controls. Each case and

control would be interviewed to determine

smoking habits, place of residence, types of

jobs, and eating habits. Case finding and selection of controls could be carried out in a fashion

similar to the congressionally mandated study

of the effects of nonnutritive sweeteners, which

focused on bladder cancer.

This size study should be sensitive enough to

detect all numerically important influences in

respiratory cancer causation. The major goals

of the study, which could be completed in 2 or 3

years, would be to:

●

●

●

●

●

generate an estimate of the contribution of

occupational factors and cigarette smoking

to respiratory cancer;

identify hitherto unrecognized occupational respiratory tract carcinogens;

determine more accurately the effects of

“passive smoking” on nonsmoking spouses

and children;

generate a direct estimate of respiratory

cancer onset rates in those not exposed to

tobacco, either through smoking or passive

smoking; and

obtain direct evidence about different types

of cigarettes, including the various low-tar

brands, on carcinogenesis.

OPTION 4

Consider for implementation the reccommendations made by congressionally mandated commissions and studies for the improvement of Federal environmental health

data collection activities.
Ch. 1–Summary ● 2 3

Congressional and executive branch concern

about the adequacy of environmental health

data has resulted in the establishment of several

advisory groups and studies. Although relatively new, they have already made numerous recommendations for improving Federal environmental health data collection and management.

In particular, consideration might be given to

recent recommendations made by the Task

Force on Environmental Cancer and Heart and

Lung Disease and in the NCHS report, Environmental Health.

The Task Force recommended:

1.

2.

3.

Additional research on methodology to

achieve less expensive study design and to

improve the collection and evaluation of

scientific data.

Research on the relative contribution to

disease made by substances in air, water,

and soil, in order to quantify the toxicological effects and the risks to human

health, and to develop strategies for control.

Support for environmental and occupational health education and development

of career opportunities in primary, secondary, and vocational schools, and better coordination of these activities.

NCHS suggested:

1. Several recommendation.~ concerned with

developing interagency data systems and

other data-linkage activities to improve

epidemiologic study capacity.

2. Procedures and legislation to facilitate the

sharing of data among Federal agencies

while safeguarding the rights of all individuals.

3. Establishing a mechanism for evaluating

priorities in Federal environmental health

activities.

Additional recommendations for improved

data collection are contained in a report of the

Institute of Medicine to DHHS. This planning

document on the Costs of Environment-Related

Health Effects will serve to guide DHHS in its

ongoing study mandated by the Health Services

Research, Health Statistics, and Health Care

Technology act of 1978.

Specific comments about the effects of the Privacy Act and the Tax Reform Act of 1976 on epidemiologic research are to be found in the Report of the Work Group on Records and Privacy

of the DHEW Interagency Task Force on the

Health Effects of Ionizing Radiation. In addition

to suggesting changes in those two acts, the

Work Group also discussed changes in the medical records law and the advantages of extending

the National Death Index back in time to include

deaths that occurred before 1979. Although the

report was concerned with radiation risks, its

recommendations are applicable to cancer epidemiology in general.

One means of centralizing environmental

health data collection activities is to establish a

center to coordinate the data collection activities of the Federal Government. With representation from various research and regulatory

agencies, the center could provide a mechanism

for setting national monitoring priorities. The

center would also be in an ideal position for

directing research to improve technologies for

measuring exposure to environmental agents

and to reduce information gaps and duplicative

efforts.

The congressionally mandated coordination

and review efforts have already been productive, and continuing them has the advantage of

building on a base of experience. Congress requires periodic reports from them, and through

those and its other oversight responsibilities,

Congress can monitor the performance of the

advisory groups and studies.

Alternatives for fostering development of

short-term tests and an option to expand support of NTP.

OPTION 5

Encourage NTP to pursue the development

of tests to replace the long-term carcinogenicity bioassay in small mammals.

Improvements in the design and execution of

carcinogenicity bioassay in small laboratory

animals have been accompanied by increased

acceptance of the results as being predictive for

human effects. The tests are used worldwide,
— — ——

24 ● Technologies for Determining Cancer Risks From the Environment

scientists continue to discuss and refine them,

and in the United States, NTP has improved the

management of the Government test program.

Despite all this progress, no improvements are

expected in two aspects of the tests: they are expensive (up to $1.0 million for each substance

tested) and they require a great length of time

(from 3 to 5 years).

In its first annual plan (1979), NTP identified

the development and validation of less expensive, quicker tests as a priority goal. NTP has

outlined a testing scheme involving both shortterm and long-term tests and is working to decide which short-term tests work best for identifying a number of toxics, including carcinogens. The attention paid to short-term tests by

NTP promises that progress will be made. The

concentration of DHHS toxicological expertise

in NTP and the development of NTP’s working

relationships with agencies outside DHHS assure that the program can call on the appropriate people in pursuing the goal of new tests.

Congress might encourage short-term test development and validation in its oversight activities, and it might consider additional funding

for the programs. There is currently a great deal

of interest in the short-term tests and additional

congressional support might have a profound

effect on their development.

A potential disadvantage of relying on NTP

for guiding and directing this research and development effort is that NTP has many other responsibilities. As discussed in this assessment

and in option 7 below, NTP also is responsible

for the management of large animal test programs. As a part of a multipurpose program,

short-term test development has to compete for

resources with other parts of the NTP. If it were

decided that short-term tests are sufficiently important to be set apart from other NTP activities, the following option might be considered.

OPTION 6

Establish a commission to advise the Federal Government about optimal methods for

development of short-term tests.

A commission, composed of experts from

academe, industry, public interest groups, and

Government agencies could be established to

make recommendations about short-term tests.

This would have the advantage of concentrating

the talents of diverse people on test development

and bringing increased attention to the tests.

The existence of a commission would probably result in short-term tests being given higher

priority in NTP. The exact tasks of the commission would be decided by NTP and other parties

with interest in the tests. However, one task

might be the serious consideration of which, if

any, tests offer promise as substitutes for longterm animal carcinogenicity bioassays when

making regulatory decisions. The establishment

of criteria that a single test or a combination of

tests would have to meet to be considered for

regulatory decisionmaking would be a spur and

a guide to test development. The possible disadvantage of a commission is that it may provide

nothing different from what NTP (as in the previous option) might provide.

The commission could focus attention on the

tests, the most likely ways for their employment

and what criteria they must meet. Adoption of

this option would reinforce the conclusions

already reached by many experts that the shortterm tests show great promise. In a major way,

the commission might answer the question

“promising for what?”

OPTION 7

Expand support of the National Toxicology

Program.

NTP has made a promising start at managing

DHHS’ short-term testing and animal toxicology. Programs. AS mentioned above, it has identified the desirability of obtaining alternatives

to the current carcinogenicity bioassay, and

whether the direction of that effort remains

within NTP (option 5) or is shared with a commission (option 6), NTP personnel will continue

to be involved in test development. In addition

to short-term test research, NTP administers the

largest animal test program for carcinogenicity.

Those expensive and time-consuming tests are

used for two general purposes: to test substances that are of interest to regulatory agencies and to provide information useful in developing and validating possible new tests.
Ch. 1–Summary ● 2 5

NTP has been successful in organizing expert

advice for its programs. It has assembled a

board of non-Government scientists to advise

the overall program, a panel of regulatory agency representatives to aid in selecting chemicals

for animal carcinogencity bioassay, and, most

recently, a panel of nongovernmental experts to

review the results of animal tests for carcinogenicity. Each of these efforts increases the

sources of advice for NTP, and assures NTP

higher visibility.

Arguments for encouraging and expanding

NTP center on its promising start, its attention

to immediate testing needs through the bioassay

program, and from the possibility of future

payoffs from new test development. Its establishment of advisory committees of Government and private sector representatives helps

assure that it will remain responsive to national

needs. A possible disadvantage of NTP is that

its wide purview and efforts both to develop test

methods and to serve the needs of the regulatory

agencies may stretch it too thin. Continued congressional interest and oversight can help avoid

this possibility.

Options concerned with EPA’s implementation of TSCA:

The following three options discuss collection

of sufficient information to protect the public

from unreasonable risks, as required by TSCA.

The first option is to provide additional support

to EPA, The second and third options consider

changes in TSCA.

OPTION 8

Increase the resources available to EPA to

enable it to assess more effectively potential

risks from substances before they are introduced into commerce and from substances

already present in commerce.

One of the most important tools for protecting the public from toxic substances is provided

in the sections of TSCA which enable EPA to

gather information about substances before

they are introduced into commerce. The

mechanism for obtaining this information is the

PMN which must be submitted to EPA 90 days

before a manufacturer or processor can produce

or import a substance. EPA must then evaluate

the PMN to determine whether or not the submitted information supports a conclusion that

the substance “may present an unreasonable

risk. ” If the decision is made that a substance

may present such a risk, EPA can then require

submission of additional information before

allowing introduction of the substance into

commerce.

EPA, which bears responsibility for evaluation of PMNs, is overburdened. EPA estimated

that 1,500 people were necessary for the program in fiscal year 1979; 382 permanent positions were authorized; 313 were filled.

A GAO report characterized EPA’s progress

in implementing TSCA as “disappointing,” and

drew attention to too few staff members as part

of the problem. If more resources are not made

available, review of PMNs will likely become

less complete, because more are being submitted. EPA estimates that 800 PMNs, almost

twice the number in fiscal year 1981, will be

submitted in fiscal year 1982.

The premanufacturing review program is designed to screen out risky substances before they

enter commerce. Making decisions at that point

is more protective of public health, and has the

additional advantage of identifying hazards

before industry had tied up large amounts of

money in manufacture and distribution. Realization of these objectives apparently will require more people as the burden to review

PMNs increases at EPA.

Other sections of TSCA specify that EPA can

require that industry test substances already

present in commerce that “may present an unreasonable risk. ” Congress, through TSCA, established the Interagency Testing Committee

(ITC) to recommend chemicals for testing, and

to date EPA has considered only ITC-recommended substances for testing requirements.

Even so, EPA has fallen behind schedule in

meeting its requirements to develop test rules.

One criticism leveled at EPA’s process of developing a test rule is that it spends more effort

than necessary to make the case that a substance

“may present an unreasonable risk. ” If the

criticism is correct, EPA may be able to improve
26 ● Technologies for Deterrnining Cancer Risks From the Environment

its procedures and reduce the time and effort

necessary to produce test rules. However, even

if that is possible, the same EPA program which

is overburdened by the PMN process is also responsible for developing test rules.

A critical problem in implementing TSCA has

been understaffing. Additional resources should

improve EPA’s performance in meeting the requirements of TSCA..

OPTION 9

Amend TSCA to require industry to submit

to EPA at least a minimal amount of information about each new chemical in PMNs.

Implementation of this option would allow

EPA to assess more effectively the potential

hazards of new chemical substances. It would

require manufacturers or processors to provide

a “base set” of information including some information about toxicity. Such important information is not required and is often lacking in

PMNs that are submitted under the current law.

Its inclusion would allow EPA to assess hazards

more completely and efficiently. Information

requirements could remain flexible to meet

varied needs, and EPA might be granted authority to exclude from this requirement those chemical categories not considered to pose a risk.

Requiring industry to generate a base set of

information is viewed by some as costly and

burdensome. There is also the additional issue

of whether the increased costs would retard innovation and keep potentially useful chemicals

off the market. However, the system is deemed

feasible by other organizations. The Organization for Economic Cooperation and Development, in which the United States participates,

has recommended that its member nations

adopt a similar system.

OPTION 10

Amend TSCA to shift from Government to

industry the burden of proof for demonstrating that additional testing is unnecessary for existing chemical substances suspected of being toxic.

EPA is slow in requiring industry to generate

toxicity information about chemicals suspected

of presenting an unreasonable risk. An amendment to TSCA that shifts much of the burden of

proof for demonstrating an “unreasonable risk”

from the Federal Government to manufacturers

and processors of chemical substances might improve EPA’s capability to reach the goals established by TSCA.

To decide about risks associated with pesticides, EPA established the “rebuttable presumption against registration” (RPAR) process which

places much of the burden of proof on industry.

Under the RPAR process, once a preliminary

finding is made that a substance “may present

an unreasonable risk” and that available information is insufficient to perform a reasoned

evaluation, industry has to produce evidence

that the pesticide does not present such a risk or

the pesticide is no longer allowed in commerce.

TSCA could be amended to permit a similar approach to other substances.

The strength of the RPAR process is that if

EPA determines that a pesticide reaches or exceeds specific risk criteria, it is the responsibility

of registrants and other interested parties to offer rebuttal evidence within a given time period.

A system patterned in concept after RPAR could

be incorporated into TSCA to alleviate much of

the burden on EPA and speed the process along.

The term “concept” is emphasized because the

RPAR approach has not so far resulted in an expeditious review of pesticides. Congress may

want to examine carefully EPA’s current efforts

in regard to pesticides and consider the National

Academy of Science’s recommendations for improving the RPAR process.

A major disadvantage of this option stems

from differences between the universe of substances covered under TSCA and the narrower

range of substances covered by the Federal Insecticide, Fungicide, and Rodenticide Act. All

pesticides are biologically active and, as a class,

they are expected to more frequently be toxic

than chemicals in general. An RPAR-like process, which requires EPA to develop only a mini-
Ch. l–Summary ● 2 7

mal amount of information about hazards

posed by substances which are already suspect,

may be more appropriate to pesticides than the

wide spectrum of substances regulated under

TSCA.

An option concerning the mechanism by

which technical decisions are made about hazard and risk for regulatory purposes.

OPTION 11

Consider establishment of a central panel

for making technical decisions for regulatory purposes.

A number of organizations, including the

Office of Science and Technology Policy, the

American Industrial Health Council (a trade

association), and some members of Congress

have - proposed the establishment of a panel

either to make decisions about carcinogenicity

for all regulatory agencies or to review all contested decisions. Consumer, environmental, and

labor groups, and the Federal regulatory agencies oppose these suggestions and favor that the

regulatory agencies continue to make their own

decisions about which substances pose risks.

The arguments advanced pro and con about the

panel are discussed above and in other parts of

the assessment. In brief, proponents hold that

scientific decisions about toxicity and risk can

be made separately from policy decisions about

regulation and find merit in a single panel making scientific decisions for all agencies. The opponents see the division between science and

policy as illusionary when making decisions

about cancer and see each agency as capable of

making its own technical decisions. Furthermore, they view a panel as a layer of unnecessary bureaucracy.

Congress is aware of this controversy and has

mandated a study of the feasibility of a panel.

The study is to be completed in June 1982, and

should produce a great deal of information

about the pros and cons of a panel. Congress

could require that the study investigate past

controversial decisions to see if scientific errors

would have been prevented by a science panel.

The objectives of the congressionally mandated study are to:

●

●

●

●

assess the merits of an institutional separation of the scientific functions of developing objective risk assessment from the regulatory process of making public and social

policy decisions;

consider the feasibility of unifying risk

assessment functions;

consider the feasibility of developing coherent risk assessment guidelines for use by

all regulatory agencies with decisionmaking responsibility; and

address relevant procedural and institutional issues that may arise in the interaction between the suggested programs of

risk assessment and the regulatory process.

In addition to those important subjects, an examination of controversial decisions to determine if scientific or technical mistakes have been

made in the past would shed light on the necessity for such a panel.

It may be that Congress is satisfied that hearings and expert opinions have already produced

sufficient information- to consider the merits of a

central technical panel before this study is completed. If a panel were established, it would initiate a new system that will be seen as a turn

away from the procedures of the past. In some

people’s view, those procedures have produced

unnecessary regulations, and a panel would be

seen as a mechanism to improve regulatory decisionmaking and, perhaps, reduce the regulatory burden. Others would see the panel as a

further obstacle in the path of producing regulations to protect the public health.
Cancer Incidence and Mortality
—-

Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Cancer Biology . . . . . . . . . . . . . . . . . . . . . . . . 33

Classification of Neoplasms. . . . . . . . . . . . . . . 34

Reducing Cancer’s Impact . . . . . . . . . . . . . . . . 35

Cancer Rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Population Estimates. . . . . . . . . . . . . . . . . . . . 36

Mortality Data . . . . . . . . . . . . . . . . . . . . . . . . 37

Incidence Data. . ., . . . . . . . . . . . . . . . . . . . . . 37

Error and Bias in Mortality and Incidence

Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Incidence and Mortality Trend Analysis . . . . . . . 42

Trends in Site-Specific Cancer Rates . . . . . . . . . . 51

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

LIST OF TABLES

Table No. Page

3. Estimated New Cancer Cases and Deaths

by Sex for Major Sites, 1981 . . . . . . . . . . . . . . 31

4. Ranked Causes of Death by Life Stages,

United States,1977 . . . . . . . . . . . . . . . . . . . . . 32

5. Death Rates per 1,000 Females, 1935

and 1975. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

6. Areas Covered by theThree National

Cancer Surveys and the Surveillance,

Epidemiology, and End Results Program

of NCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

7. Age-Adjusted Cancer Incidence Rates per

l00,000 Population for Selected Sites by Sex

and Year, and Average Annual Percent

Change, TNCS Areas 1969-71 and SEER Areas

1973-76: Whites . . . . . . . . . . . . . . . . . .......50

8. U.S. Age-Standardized Cancer Death Rates

for Males and Females Under 65, 1953-78 . . . . 52

9. U.S. Age-Standardized Cancer Death Rates

for Males and Females Over 65, 1953-78 . . . . . 54

LIST OF FIGURES

Figure No. Page

1. Comparison by Race and Sex of Percent

Net Census Undercounts, by Age, 1960

and 1970. . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Figure No. Page

2.

3,

4,

54

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Age-Adjusted Cancer Incidence Trends

Among Males for All Sites Combined

Showing the Most Frequent Sites. . . . . . . . . . 44

Age-Adjusted Cancer Incidence Trends

Among Females for All Sites Combined

Showing the Most Frequent Sites . . . . . . . . . . 45

Site-Specific Cancer Incidence Rates per

Million Males, Alleges.. . . . . . . . . . . . . . . . 46

Site-Specific Cancer Incidence Rates per

Million Females, All Ages. . . . . . . . . . . . . . . 47

Site-Specific Cancer Mortality Rates per

Million Males at Ages O-64 Years: 1953-57;

1963-67; and 1973-77. . . . . . . . . . . . . . . . . . . 48

Site-Specific Cancer Mortality Rates per

Million Females at Ages O-64 Years:

1953-57; 1963-67; and 1973-77. . . . . . . . . . . . 49

Mortality Rates for All Malignancies per

l00,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 51

Respiratory Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

population: 1950-77 . . . . . . . . . . . . . . . . . . . 56

Trends Since 1950 in U.S. Male Lung

Cancer Mortality at Young Ages . . . . . . . . . . 56

Combined Mouth, Pharynx, Larynx, and

Esophagus Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 57

Stomach Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 57

Combined Small Intestine, Colon, and

Rectum Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 57

Pancreas Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 58

Breast Cancer Mortality Rates per 100,000,

Age-Standardized to U.S. 1970 Population:

1950-77. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Uterus Cancer Mortality Rates per

100,000, Age-Standardized to U.S.

1970 Population: 1950-77 . . . . . . . . . . . . . . . 59

Prostate Cancer Mortality Rates per

100,000, Age-Standardized to U.S. 1970

Population: 1950-77 . . . . . . . . . . . . . . . . . . . 60
2

Cancer Incidence and Mortality

INTRODUCTION

In 1979, cancer killed more than 400,000

Americans (254) and 765,000 new serious cancers’ were diagnosed (6) (see table 3). Over 3

million Americans alive today have had a diagnosed cancer. Cancer accounts for about 20 percent of total U.S. mortality, second only to

heart diseases, which are responsible for about

38 percent of deaths. Moreover, cancer is the

number one killer of adult Americans, ages 25

to 44 (see table 4).

Of equal or greater importance than knowing

the number of cancers and cancer deaths is the

matter of whether age-specific cancer rates are

increasing, decreasing, or remaining constant.

Are people of a given age at greater risk of

developing cancer today than were people of

that age in the past? This question of changing

rates bears on whether aspects of the modern en-

‘Not including nonmelanoma skin cancers, estimated at 400,000

per year.

vironment, largely introduced within the last

two to four decades, might be causing today’s

cancers. If so, preventive efforts should start by

identifying these elements in the environment

and modifying them. If most of the now common cancers have been common for a long time,

it might suggest that the causes of cancer have

not changed greatly. In that case, prevention

might require changes in long-established

aspects of the American lifestyle.

When seeking means to prevent cancer, special attention must be given to increases in cancers at particular sites. This attention is warranted because the increase indicates that the

cause (or causes) might have been introduced

recently and can presumably be identified and

eliminated. However, to concentrate on a search

for new agents to the exclusion of other causes

may ignore the possibility of preventing presTable 3.—Estimated New Cancer Cases and Deaths by Sex for Major Sites, 1981

Females Males

Total cases Total deaths Cases Deaths Cases Deaths

Percent Percent Percent Percent Percent Percent

Site Number of total Number of total Number of total Number of total Number of total Number of total

Lung . ........122,00 0

Colon-rectum .. 120,000

Breast . .......110,90 0

Prostate . . . . . . 70,000

Uterus . . . . . . . . 54,000

Urinary . . . . . . . 54,600

Oral (Buccal

cavity and

pharynx) 26,600

Pancreas. . . . . . 24,200

Leukemia . . . . . 23,400

Ovary. . . . . . . . . 18,000b

Skin . . . . . . . . . . 14,300

All others . ....177,000

15.0

14.7

13.6

8.6

6.6

6.7

3.3

3.0

2.9

2.2

1.8

21.7

105,000

54,900

37,100

22,700

10,300

18,700

9,150

22,000

15,900

11,400

6,700

106,150

25.0

13.1

8.8

5.4

2.5

4.5

2.2

5.2

3.8

2.7

1.6

25.3

34,000

62,000

110,000

—

54,000

16,600

8,200

11,500

10,400

18,000

7,300

80,000

8.3

15.0

26.7

—

13.1

4.0

2.0

2.8

2.5

4.4

1.8

19.4

28,000 14.5

28,700 14.9

36,800 19.1

— —

10,300 5.4

6,500 3.4

2,850 1.5

10,500

7,000 ::;

11,400 5.9

2,700 1.4

47,750 24.8

88,000

58,000

900

70,000

—

38,000

18,400

12,700

13,000—

7,000

97,000

21.8

14.4

0.2

17.4

—

9.4

4.6

3.2

3.2—

1.7

24.1

77,000 33.8

26,200 11.5

300 0.1

22,700 10.0

— —

12,200 5.4

6,300 2.8

11,500 5.1

8,900 3.9 — —

4,000 1.8

58,400 25.7

Total . ......815,00 0 420,000 412,000 192,500 403,000 227,500

alnvasive cancer only.

bMelanoma only.

NOTE: Estimates of new cancer cases and deaths are offered as a roQgh guide and should not be regarded as deflnitwe

SOURCE: American Cancer Society, 1980.

31
Table 4.—Ranked Causes of Death by Life Stages, United States, 1977

(based on age-specific death rates)

Age group

Total Adolescents/ Older

population Infants Children young adults Adults Adults adults

Cause of death (all ages) (under 1) (1-14) (15-24) (25-44) (45-64) (over 65)

Chronic diseases

Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 2 — 3 5 1 2 2

Heart disease . . . . . . . . . . . . . . . . . . . 1 — 6 2 1 1

Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . 3 — 8

b

9 8 3 3

Arteriosclerosis. . . . . . . . . . . . . . . . . . 9 ’ — — — 5

Bronchitis, emphysema and

— —

asthma . . . . . . . . . . . . . . . . . . . . . . . — — — — 10 8

Diabetes mellitus . . . . . . . . . . . . . . . .

—

7 — — 10 10 8 6

Cirrhosis of the liver . . . . . . . . . . . . . . 8 — — — 7 4 9

Infectious diseases

Influenza and pneumonia. . . . . . . . . . 5 2 6 8 9 9 4

Meningitis . . . . . . . . . . . . . . . . . . . . . . — — 8

b

Septicemia. . . . . . . . . . . . . . . . . . . . . . —

— — — —

3 — — — — —

Trauma

Accidents:

Motor vehicle . . . . . . . . . . . . . . . . . . 6 — 2 1 3 7 10

All other . . . . . . . . . . . . . . . . . . . . . . 4 1 2 4 5 7

Suicide . . . . . . . . . . . . . . . . . . . . . . . . . 9

a — 10 3 5 6 –

Homicide . . . . . . . . . . . . . . . . . . . . . . . — — 5 4 6 – –

Developmental problems . . . . . . . . . . — 1 4 7 — — —

‘Rates for arteriosclerosis and slllcide are at about the same level In the total Population.

bRates for Meningltls and stroke are at about the same level arnon9 children aged 1 to 14

SOURCE Public Health Service (299)

ent-day cancers which are due to factors prevalent in the Western World since the last century

or before.

Apart from whether or not cancer rates are

changing, many variables contribute to the

greater prominence accorded the disease today

as compared to even a few decades ago. A major factor in its emergence is the sharp decrease

in deaths from infectious diseases such as tuberculosis, dysentery, and diphtheria over the past

150 years. Before the mid-19th century, these

diseases killed far more people than did chronic

diseases. General improvements in living conditions, public sanitation, and nutrition began to

reduce the rates of infectious diseases, and the

decline was hastened by advances in biology

and medicine early in the 20th century.

As the decades passed, these improvements

have shifted the age structure of the population

upward. As a result, there is a larger proportion

of people over 65, and cancer risks have always

been 10 or 100 times greater among them than

among younger people. This increases the actual number of cases and deaths (crude incidence

and crude mortality) but not necessarily the agestandardized cancer rates.

Second, cancer has become relativel y more

common as a cause of death because of the prevention or cure of other diseases. This phenomenon is illustrated by the mortality data for

females in 1935 and 1975 (see table 5). Nonrespiratory cancer death rates decreased substantially, but the death rates from all other causes

decreased even more. Therefore, the percentage

of female deaths attributable to nonrespiratory

cancer was greater in 1975 than 40 years earlier,

even though female cancer risks had declined

during that period.

Third, many cancers, which might previously

have gone unnoticed, are now diagnosed both

during medical treatment and in subsequent

death certification. This change is especially

pronounced among the elderly who today receive more medical attention than in premedicare years.
Ch. 2—Cancer lncidence and Mortality ● 33

Table 5.–Death Rates per 1,000 Females, 1935 and 1975

All causes except All nonrespiratory Respiratory tract

Year cancer cancers cancers All causes

1935

(1933-37) . . . . 11 .92a (87.6 °/o)

b

1.65 (12.1 0/0) 0.03 (0.2°/0) 13.60 (lOOO/o)

1975

(1973-77) . . . . 4.96 (78.80/o) 1.17 (18.670) 0.16 (2.50/o) 6.29 (lOOO/o)

~All ages, age-standardized to Ihe U.S. 1970 census population.

“Percentage of rate for all causes

SOURCE: Doll and Peto (93).

Finally, cancer is discussed more openly in the

media and among friends and relatives of cancer

patients; public figures no longer try to conceal

their diseases. Previously, such matters were

often hushed up and the diagnosis perhaps withheld even from the victim. The jump in the reported incidence of breast cancer in 1974 and

1975 is attributed to the publicity surrounding

Happy Rockefeller’s and Betty Ford’s breast

cancer surgery. Greater public awareness led to

more women being examined and the detection

of more cancers, but the reported increase in

those years is not considered to reflect a real increase in incidence.

Cancer has a major impact on the Nation’s

economy, both from the personal costs of treatment and lost income, and from public expenditures for screening programs, public education,

and cancer research. In 1977, the most recent

year for which information is available, direct

costs for all cancers, including hospital care and

physicians’ services, amounted to about 7 percent of these costs for all illness (168). Indirect

costs, based on a lost earnings approach (discounted at 6 percent), amounted to approximately 19 percent of total indirect costs (preliminary estimate; 168). The costs of cancer are

not exclusively economic, though these are

enormous. Social costs have taken on increasing

prominence in recent years, and include more

than the obvious pain and suffering of the victim. Relatives and friends of victims and care

givers may suffer direct consequences of the victim’s morbidity and mortality. Social isolation,

economic dependence, lost personal and business opportunities, and many undesirable

alterations in lifestyle are inevitable. Serious

emotional and psychological problems requiring professional attention are not uncommon

among victims and their family members, often

producing irreversible changes in family structure and relationships.

A common measure of disease impact is the

number of years of life lost due to premature

mortality. This index takes into account both

the number of deaths and the age at which people die. Therefore, the death of a younger person will contribute more person-years lost than

will the death of a person who is closer to having lived to full life expectancy. Cancer accounted for approximately 19 percent of all

deaths in 1975, and about 16 percent of all years

of life lost (308), indicating that the average age

of those who die from cancer is greater than the

average age of those who die from the aggregate

of all other causes of death.

Cancer Biology

The 200 or so human cancers are diseases in

which some cells replicate out of control of normal growth processes. Such cells produce millions of similar self-replicating descendent cells.

The cancerous state is reached when parts of

this cell mass cross the boundaries of their “normal territory” and invade neighboring tissue

directly, or travel to distant sites through the

circulatory system. This event is called metastasis. The ability to invade or to metastasize

characterizes these tumors as malignant, or

cancerous, in contrast to benign tumors which

remain confined to the tissues in which they

arise, The possibility of complete surgical removal and cure is very high for benign tumors,

with some notable exceptions, but declines

precipitously with metastasis.
34 ● Technologies for Determining Cancer Risks From the Environment

Over the past several years, a preponderance

of evidence has accumulated supporting the

view that cancers may arise from single cells, a

conclusion reached after long debate. This

evidence means that changes occurring in only 1

of the 10 trillion cells in the body can initiate a

tumor. However, not all cells are at equal risk,

which is obvious from the orders of magnitude

differences in the occurrence of cancer at different sites (see table 3).

Certain characteristics of cells have been identified as contributing to the observed differences. The rates of cell growth and division in

adults vary from organ to organ, from constant

and fairly rapid multiplication, to none at all.

Some common cancer sites, particularly the

gastrointestinal tract, skin, and bone marrow,

are those at which regular cell division occurs

throughout life. The cells of other organs, for

example those of the liver, and cells of the

thyroid and other glands seldom multiply but

retain that capability to repair tissue damage.

They are important, but somewhat less common, cancer sites. At the other extreme, nerve

cells have no capacity for multiplication at

maturity, and cancers of these cells are not

found in adults. This distinction is not a rigid

one, but the rate of cell division contributes in

some way, at least in many sites, to the total

probability y of cancer development.

Another determinant of the frequency of cancer at different sites seems to be the degree of exposure of the cells to outside influences. More

than half of all cancers arise in external epithelial cells which are in direct contact with the outside environment. The sites affected are mainly

the skin and the linings of the gastrointestinal

tract, lung, and cervix. This observation supports the view that most cancers are caused by

the environment and are not simply inevitable

consequences of the aging process. (For a general discussion of cancer biology, see Cairns (42). )

Cancer causation is thought to involve several steps. The simplest multistage process consists of two parts: initiation and promotion. Initiation is seen as occurring in response to an external stimulus and produces a cell that is

“latently premalignant” (302). The initiation

event may be a mutational change in the cell’s

genetic material, but the change is unexpressed,

i.e., it causes no detectable change in the cell’s

growth pattern. “Initiated cells can remain as

such for at least a large segment of the animal’s

life without being removed, destroyed, or otherwise harmed in any measurable way” (116)1,

In laboratory experiments, exposure of an initiated cell to another substance, a promoter,

converts the cell to an “irreversible malignancy”

(302). Promoters convert only initiated cells to

tumor cells and have no lasting effect on noninitiated cells. (A review and discussion of current

research about initiation and promotion can be

found in 240. )

Many different agents may be initiators or

promoters or both, and depending on an individual’s exposures, years may elapse between

initiation and promotion. The introduction of a

potent initiator into society this year might

cause no detectable increase in cancer for several years because of the rarity of the required

subsequent promotion stage. Alternatively, a

potent promoter that interacts with previously

initiated cells might result in an increase being

seen in a shorter time.

Classification of Neoplasms

There are three main classes of malignant

neoplasms. Cancers of the epithelia, including

the external epithelia and the internal epithelia

which line various glands, are called carcinomas. These afflictions account for over 90 percent of all cancers, excluding the common, but

not usually fatal, nonmelanoma skin cancers.

The remaining cancers are either sarcomas

(cancers of supportive tissues, e.g., bone, muscle, tendon, cartilage), or leukemias and lymphomas (cancers of circulating cells).

Cancers in these broad categories are conventionally recognized and recorded by the site at

which they occur and by the cell type of the

malignancy, and are regarded, for the most

part, as separate disease entities. As knowledge

of causation of specific cancers has improved,

and definite associations elucidated between exposures and the development of cancers, it has

become clear that sites are selectively affected

by particular exposures and behaviors, and the
Ch. 2–Cancer Incidence and Mortality ● 35

classification system has some validity for considering preventive strategies.

Reducing Cancer’s Impact

There are three approaches to reduce cancer’s

impact: prevention, the ultimate goal; earlier

detection; and improved treatment. The general

consensus that most cancers are caused by extrinsic forces has led to the view that many cancers are preventable. Estimates of theoretically

preventable cancers have reached as high as 90

percent of the total, though the practical limits

undoubtedly will be lower.

Once identified, exposures to carcinogens

may be reduced either through voluntary or

regulatory methods. There has been one notable

success among efforts to influence personal behavior—reduction in cigarette smoking among

adults. The decrease is most notable among

adult males, and can confidently be attributed

to the publicity and attention given to adverse

health effects of tobacco. Between 1965 and

1979, the proportion of adult male smokers

dropped from 51 to 37 percent. The decline

among women over the same period was much

smaller, from 33 to 28 percent (287).

It is generally believed that American eating

habits are healthier than they were early in this

century and that some of the changes, though

not specifically identified, may have spurred the

decrease in stomach cancer rates. Future cancerreducing changes in dietary habits may result

from research into mechanisms by which dietary components cause or prevent cancers, or

from epidemiologic observations of associations

between dietary components and cancers.

About two dozen laws provide for the regulation of carcinogenic agents to protect public

health. Through them, exposures to some 100

chemicals are controlled. (Ch. 6 describes laws

and regulation. )

Early detection of cancers may improve overall survival rates when efficacious treatment is

available. Localized cancers detected before

they metastasize can be excised completely,

leaving the patient with an excellent chance for

survival. Between the early 1950’s and the late

1960’s, the proportion of prostate cancers diagnosed as “localized” increased from 48 to 63 percent. Over that period, the 5-year relative survival for prostatic cancer climbed from 43 to 57

percent. The overall relative survival rate is the

ratio of the observed survival rate of the treated

group to the expected survival rate for persons

of the same age, sex, and race in the general

population. Three elements may contribute to

the apparent improvement. Part may be artifactual and result from detecting less serious

tumors in the late 1960’s, that, had they occurred in the early 1950’s, would not have come

to clinical attention. Some of the improvement

probably resulted from better treatment. However, a major component of the gain resulted

from detection of tumors at earlier stages when

they could be more successfully treated (247).

Surgery, radiation therapy, and chemotherapy are the mainstays of cancer treatment. Vincent DeVita, Director of the National Cancer Institute (NCI), asserted that “approximately 41

percent of patients with the more serious forms

of cancer are curable using therapies now

available . . . . By cure we mean that a patient

remains free of disease and has the same life expectancy as a person who never had cancer”

(85), Attaining a 41-percent cure rate is dependent, however, on every patient receiving optimal treatment.

Advances have occurred in all three areas:

Surgical techniques have been refined, radiotherapy is more widely available, and aggressive chemotherapy is developing and appears to

hold the greatest potential. To date, the number

of people actually helped by chemotherapy is

modest, but dramatic advances have been made

against many of the leukemias and lymphomas.

Chemotherapy, used along with surgery and

radiotherapy, has proven successful for a significant, but small, fraction of patients with

some cancers. These represent promising medical advances, but because most people who receive the drugs, which are often accompanied

by undesirable side effects, experience no gain in

life expectancy, a backlash against chemotherapy has developed (86).
36 ● Technologies for Determining Cancer Risks From the Environment

CANCER RATES

The examination of cancer rates focuses on

each body site individually, since some are increasing, some decreasing, and some remaining

more or less stable. Trends for the aggregate of

all cancers obscure these individual trends.

The trend that dominates all others is the increase in lung cancer, largely a result of the

widespread adoption of cigarette smoking

earlier in this century. Male lung cancer rates

have been rising steadily for at least half a century. Female lung cancer rates started to rise

about 25 years ago and are now increasing

rapidly. All other changes are small in comparison with the large increases in smokingrelated cancers, although the decreases in cancer

of the stomach and uterus are also important.

Currently, there is a general tendency for the

rates of change at each cancer site to be slightly

more favorable for people under 65 than for

those over 65: If the site-specific rate for all ages

is increasing, it is increasing at a slower pace

among the younger group. If the rate is decreasing, the decrease is more pronounced in those

under 65. Two clear exceptions stand out. First,

skin cancer in males is increasing much more

rapidly among people under 65 than among

those over 65. Second, mortality rates of brain

tumors appear to be moving in opposite directions. Despite falling death rates in middle age,

there are large increases in old age, perhaps

because diagnosis has improved for older

people.

If attention is restricted to those younger than

65, for almost all types of cancer except those

strongly affected by smoking (cancers of the respiratory and upper digestive tracts), the most

recent trends in mortality are downward. The

chief exceptions are pancreatic cancer in

women, and melanoma in whites of both sexes.

Incidence and mortality rates differ because

not all people who contract cancer die of it.

Rates are calculated by relating the number of

cases or deaths to the “population at risk” of

either contracting cancer or dying from the disease. “Crude rates” are the total number of cases

or deaths divided by the total population. These

rates are affected by changes in the age structure

of the population, that is, the fact that there are

more older people in the population today, and

hence more people contracting and dying of

cancer means that the crude rates will increase.

All of the overall comparisons in this report are

based on rates “age-standardized” to the composition of the population determined in the

1970 census. Changes in these rates occur

because of changes in the risk of cancer among

people of a given age; increases or decreases in

the proportion of old people in the population

do not affect age-standardized rates. When a

figure or comparison refers to a specific age

class, the rates are based on the cases or deaths

as a proportion of the total number of people in

that class.

The remainder of this chapter deals with the

data used in computing cancer rates and in analyzing trends, and some of the problems associated with those processes. A discussion of cancer at body sites of major importance follows.

Population Estimates

To evaluate changes in either incidence or

mortality over time, it is necessary to know the

population at risk, i.e., the number of people in

the United States who might contract or die

from the disease. Ideally, one would like this information cross-classified by such characteristics as age, race, and sex. More detailed information, such as the socioeconomic characteristics of the population, is also desirable.

The principal source of population data is the

Census of Population, which is carried out once

every 10 years. For each year after the census,

all years ending with 1 through 9, “postcensal

estimates” are prepared, using statistical techniques which use the data from the last census

and possibly earlier censuses, along with vital

statistics data, immigration data, and other data

relating to population change. When the next

decennial enumeration is completed, these estimates are replaced by “intercensal estimates;”

prepared by interpolation between the two) censuses. However, the intercensal estimates are
Ch. 2—Cancer Incidence and Mortality ● 37

not available until several years after the latest

census is completed. Thus, there may be large

discontinuities between the later postcensal population estimates and the actual census count—

the adjusted estimate for the number of males

age 85 or older between 1959 (postcensal estimate based on the 1950 census) and 1960 (census

enumeration) shows a 50-percent increase.

These discrepancies are not present when intercensal estimates for 1959 are compared to

1960 figures.

The censuses have been characterized by underenumerations which vary from census to

census. The undercounts are thought to be

small, near zero, for some demographic groups,

such as white females 40 to 45 years old (in

1970), but are considerably greater for other

groups, such as black males 25 to 45 years old,

for whom the estimated undercounts are on the

order of 10 percent or more (see fig. 1) (349). A

number of studies have shown that serious undercount of the population exists for the very

elderly, those age 85 years and over (350).

Mortality Data

Information on deaths has been collected

through the national vital registration system

since the beginning of this century and is the

most reliable basis for calculating U.S. cancer

rates. Since 1933, data have been collected continuously for the entire United States. National

vital statistics functions are centered in the Division of Vital Statistics of the National Center for

Health Statistics (NCHS). U.S. mortality statistics are based on information obtained directly

from copies of original death certificates received from the registration offices and from

data provided to NCHS through the Cooperative Health Statistics System. A number of

States now provide their data—medical and

demographic—entirely on computer tapes.

NCHS is not a repository of original certificates. Those are available only from the States.

U.S. mortality statistics for all years except 1972

are based on information for all deaths. In 1972,

they were based on a 50-percent sample, because of unusual budgetary and personnel constraints.

The mortality figures used in this report are

based on vital statistics information from

NCHS, which (except for the most recent years)

have been published in the annual volumes of

Vital Statistics of the United States, Volume II,

Mortality. The data refer to the aggregate population of the 50 States and the District of

Columbia.

Incidence Data

While mortality data are extremely useful for

studying cancer, incidence data are necessary to

advance the state of knowledge about when and

where cancers occur, irrespective of outcome.

Population-based cancer registries are attempts

to identify all incident cases in a defined population. In practical terms, registries cover

discrete political or geographic areas. There are

a number of countrywide cancer registries (e. g.,

Canada, Norway, and Sweden). These registries

have generally taken advantage of preexisting,

centralized data-collection mechanisms. There

is no nationwide cancer registry in the United

States. By law, cancer is a reportable disease in

about 30 States and the District of Columbia

(58), but most States have not put in place the

mechanisms necessary to handle reported data.

The most prominent efforts by States are Connecticut’s statewide registry, operating since

1935, and the New York State registry, in operation since 1940 (New York City was not included until 1973).

The first major cancer incidence surveys in

the United States were the Ten Cities Surveys of

1937 and 1947’, (now referred to as the First and

Second National Cancer Surveys, FNCS and

SNCS, respectively; see table 6), and the Iowa

study of 1950. Metropolitan areas were chosen

for FNCS and SNCS to assure a high percentage

of correctly diagnosed cases. The areas surveyed were selected to provide reliable data and

included about 10 percent of the U.S. population. The sample population was representative

of the geographic distribution of Northern,

Southern, and Western cities with populations

greater than 100,000, but was not entirely demographically representative of the U.S. population.
.

38 ● Technologies for Determining Cancer Risks From the Environment

Figure 1.— Comparison by Race and Sex of Percent Net Census Undercounts, by Age, 1960 and 1970

Percent Net Undercounts, by Age, Race, and Sex, 1960

‘“~ n h

– 5

1- White males — — \

t

White females - ● 

— 

● 

—

Black males

–10 Black females - — — —

-151__l_J_ 1 1 i 1 1 I 1 1 1 1 1 1 I

0 5 10 15 20 25 30 35 40 45 50 55 6“ 65 70 75

‘ c

15

10

E5a) o

%&

o

–~

– 10

–15

Age

Percent Net Undercounts, by Age, Race, and Sex, 1970

\\*

/ ./’ — \

- - - /

White males

White females

Blac:k males

Blac:k females

——

-e-.—

\

b

\ /

\/// \\\/ —- -— \,-/

‘1

I 1 1 I 1 1 1 I 1 I I 1 1 b 1

5 10 15 20 25 30 35 40 45 50 55 60 65 7“ 7!

Age

Note: Estimates for 1970 are based on adjusted census data, A negative sign ctenotes a net census Overcount,

SOURCE: U.S. Bureau of the Census (349)
Ch. 2–Cancer Incidence and Mortality ● 39

Table 6.—Areas Covered by the Three National Cancer Surveys and the Surveillance, Epidemiology, and End

Results Program of NCI

FNCS SNCS TNCS SEER SEER +

Area

SEER +

(1937-39) (1947-48) (1969-71) 1973-present 1-3 NCSa

TNCS b

Atlanta Cherokee, Clayton, Cobb, Cherokee, Clayton, Cobb, Clayton, Cobb, DeKalb, Fulton,

DeKalb, Douglas, Fayette, DeKalb, Douglas, Fayette, Gwinnett

Forsythe, Fulton, Gwinnett Forsythe, Fulton, Gwinnett x x x

Birmingham Jefferson Jefferson Jefferson, Shelby, Walker

Dallas Dallas Dallas Collin, Dallas, Denton, EIIis,

Kaufman, Rockwell

Denver Denver Adams, Arapahoe, Denver, Adams, Arapahoe, Denver,

Jefferson Jefferson, Boulder ——

Detroit Wayne Wayne Macomb, Oakland, Wayne x x x

Pittsburgh Allegheny Allegheny Allegheny, Beaver, Washington,

Westmoreland

San Francisco- Alameda, San Francisco Alameda, San Francisco Alameda, Contra Costa, Marin,

Oakland San Francisco, San Mateo x x x

Chicago Cook Cook

New Orleans Orleans Orleans x

c

Philadelphia Philadelphia

— —

Philadelphia —

Fort Worth Tarrant Johnson, Tarrant

Colorado Entire State

.

Iowa Entire State x x

.-

Minneapolis- Anoka, Dakota, Hennepin,

St. Paul Ramsey, Washington —

Seattle - Puget

Sound Area

(13 counties) x

Connecticut

(entire State) x

Hawaii

(entire State) x

Utah

(entire State) x

Puerto Rico x

New Mexico

(entire State)

Abbreviations: FNCS — First National Cancer Survey.

SNCS — Second National Cancer Survey.

TNCS — Third National Cancer Survey.

SEER — Surveillance, Epidemiology and End Results.

NCS — National Cancer Survey.

~“X” Indicates area was covered by all 3 NCSS and SEER.

“X” mdlcates area was covered by TNCS and SEER.

cNew Orleans IS being dropped from the SEER program in 1981.

SOURCE Devesa and Silverman (84) and Off Ice of Technology Assessment

Several changes took place in the next major

effort, the Third National Cancer Survey

(TNCS) of 1969 through 1971 (84). The reporting period was 3 years instead of 1. The

timeframe was used to improve data for rare

cancers and for smaller population groups.

Working under contract to NCI, local, nonprofit medical organizations (e.g., schools of

public health, medical schools, health department offices) conducted the project at each site.

Ten percent of the cancer patients were included

in a more intensive survey to determine methods of treatment used, duration of hospitalizaX

tion, cost of medical care, and economic impact

on the family. There was considerable geographical overlap between FNCS, SNCS, and

TNCS. Seven of the original 10 cities were included in TNCS, although coverage was expanded from only central city areas to their

Standard Metropolitan Statistical Areas. The

entire state of Iowa was added. The Commonwealth of Puerto Rico cancer registry also supplied data (see table 6).

The first nationally coordinated, continuousregistration system, the Surveillance, Epidemiology, and End Results (SEER) program, was
40 Technologies for Determining Cancer Risks From the Environment

begun in 1973 by NCI. NCI derives the SEER

program mandate from the National Cancer Act

of 1971 which directs that the Director of NCI:

Collect, analyze, and disseminate all data useful in the prevention, diagnosis, and treatment

of cancer . . . . (sec. 407(b)(4)).

In SEER areas, attempts are made to ascertain

every primary cancer, excluding nonmelanoma

skin cancer. All information pertaining to a case

is consolidated into one record, to facilitate

followup and to correlate survival data with

treatment, age, and other variables.

Eight geographical locations, four in common

with TNCS were chosen originally, and three

were added subsequently (see table 6). Recently,

one area, New Orleans, was dropped from the

program. Approximately 10 percent of the U.S.

population resides in SEER areas. A SEER report for the first 4 years of operation compared

the demographic characteristics of the population with the total U.S. population (248):

. . . the participants . . . are fairly representative with respect to age. Blacks are somewhat

underrepresented while other nonwhite populations (Chinese, Japanese, Hawaiians, and American Indians) are somewhat overrepresented.

Rural populations (especially rural blacks) are

also underrepresented.

The SEER program has considered adding

registration areas toward the goal of improving

the reliability of data for all segments of society.

Exact proportional representation is not, however, the ideal situation, since for small demographic groups overrepresentation may be necessary to produce reliable data.

As of September 1980, data were available

from the first 6 years of SEER operation. NCI

plans to publish complete incidence and mortality data every 5 years, and to make available

data for interim years. A small amount of treatment and survival data have been published as

the “Cancer Patient Survival” reports (247,251)

following the earlier “End Results in Cancer”

series. As more years of followup data are accumulated, NCI survival analyses will increasingly draw on SEER program information.

Error and Bias in Mortality and

Incidence Data

There are various sources of error and bias in

both mortality and incidence data. Reasoned interpretation of trends depends on understanding

the forces, other than true changes in incidence

and mortality, which impact on certified mortality (cause of death as reported on death certificates) and registered incidence. The important impacts are outlined below:

1.

2.

Improper diagnosis. -Individuals may

contract cancer and die but the correct

diagnosis may never be made, affecting

both incidence and mortality rates. It is

possible, for reasons of inadequate medical care or simple oversight, for lung cancer to be diagnosed as pneumonia; brain

cancer as stroke or senility, and leukemias

or lymphomas as infectious diseases. Conversely, cancer may be reported as the

cause of death for people dying of other

causes. For instance, in a 1970 autopsy

series in Atlanta, Engel et al. (99) found

that 86 percent of cancers found at autopsy were listed as the underlying cause of

death on the death certificate. A missed

diagnosis of cancer in a dying patient is

presumably more likely to occur among

old than among young cancer patients, if

only because the old are less likely to be

hospitalized. These errors are likely to

have become less numerous over the past

few decades, particularly in older people

after the introduction of medicare in 1966.

Improvements in ascertainment. —It i s

likely that fewer cancers are missed today

than in the past, affecting both incidence

and mortality rates, probably to a greater

degree in the older age groups. In addition, incidence rates may be influenced by

a progressive improvement in the readiness of physicians to collaborate with a

cancer registry. Data from the Connecticut cancer registry suggest that since its

inception in 1935, the completeness of

coverage may have improved so as to in-
Ch. 2–Cancer lncidence arid Mortality ● 41

troduce substantial upward biases into the

rates. Better ascertainment of incident

cases is also seen in comparing SNCS to

TNCS. The proportions of cases that were

ascertained by death certificate only, and

for which no clinical record was ever

found, were 11.8 and 2.2 percent, respectively (84). This suggests that the earlier

survey may have underestimated total incidence rates. Overall, there is a tendency

for better recording of cases over time,

which causes an apparent increase in incidence.

3. Primary site not specified. —The site of

the primary cancer in patients with metastatic disease may never be determined. Six

to eight percent of American cancer death

certificates are for cancer of an unspecified

primary site (255). This percentage is a

little lower among whites than among

nonwhites, and among middle-aged than

among older people, but it has not materially changed for decades, and may not

seriously bias the assessment of trends in

cancers at specified sites. However, the

more than 20,000 cancer deaths per year

now classified as unspecified represent an

uncomfortably large amount of missing

information.

4. Incorrect primary site or cell type. —

Misdiagnosis of the primary site or cell

type of fatal cancer is probably the most

important bias affecting cancer death certification rates. Patients with cancer of

one primary site (e. g., lung) may be misdiagnosed as having a cancer originating

from another site (e.g., pancreas or

brain), if the cancer has either extended

itself to other nearby organs, or metastasized to distant organs. Boyd et al. (93),

concluded that at ages over 65 most bone

tumor deaths were in fact misdiagnosed

secondaries from other sites. This may

also have been true in the past for liver

cancer, since bone and liver are not sites

where cancers commonly arise but, along

with brain and lung, are sites to which

cancers commonly spread. Likewise, cancers of one particular cell type may be

misdiagnosed as cancers of another cell

5.

6.

7.

type. This problem can sometimes be circumvented by grouping together particular types of cancers which are often misdiagnosed as each other, e.g., all benign

and malignant brain tumors or all colon

and rectal cancers. Colon and rectum cancers, which together account for 18 percent of cancer deaths, are often lumped

together to improve the reliability of the

statistic. However, they are different diseases and their individual characteristics

are obliterated by this procedure.

Incomplete transfer of information to

death certificates. —Even if the cancer is

correctly diagnosed while the patient is

alive, the correct information may never

reach the death certificates. Percy,

Stanek, and Gloeckler (291) tabulated correspondence between the primary site of

cancer, as diagnosed in the hospital, and

the primary site as it eventually appeared

on the death certificate for 48,826 patients

in TNCS. Many discrepancies emerged.

Cancers of the colon were overreported

while cancers of the rectum were underreported on death certificates as compared

to hospital records. In addition, in over 50

percent of all cases where a more specific

cancer site (cecum, ascending colon and

appendix, transverse colon, etc. ) appears

in hospital records, it was recorded differently—most often as “colon, not otherwise specified’’—on the death certificate.

Cancers of specific uterine sites (cervix

and corpus) suffer from the same problem. Cancers of the buccal cavity are

underreported on death certificates, while

bone cancer is overreported, and other

sites are misreported to varying degrees.

Inclusion of prevalent cases. —This bias is

limited to incidence data. In a study which

runs for a relatively short period, “prevalent” cases, which were actually diagnosed

before the start of the study period, may

inadvertently be included. This was more

likely a problem in FNCS and SNCS,

somewhat less so in TNCS, and less still in

the ongoing SEER program.

Changes in the definitions for some cancers. —The definition of what constitutes a

90-4 B 1 9 - B 1 - 4
42 ● Technologies for Determining Cancer Risks From the Environment

cancer changes with increasing knowledge. For instance, all salivary gland tumors, whether malignant or of mixed cellularity, were classified as cancer up to

1967, but the mixed tumors were dropped

thereafter. Likewise, all brain tumors were

counted in SNCS, while only those specified as malignant were included in TNCS,

causing a substantial artifactual decrease

in brain tumor incidence between the two

surveys (84).

8. Increased access to medical care and

changes in diagnosis. —An even more

serious bias stems not from classification

changes but from the more vigorous

search for lumps, and improvements in diagnostic procedures which affect mainly

incidence rates. By old age the human

body may contain various lumps which, if

examined histologically, would be classified as cancer, yet many are biologically

benign and cause no reductions in lifespan. For instance, by age 70, 2.5 percent

of males in the areas covered by TNCS

were diagnosed as having prostatic cancer, while at autopsy 25 percent of males

aged 70 or over who died of unrelated

causes were found to have cancerous prostates (33). Similarly, among women undergoing mastectomy for cancer of one

breast, and in whom cancer is not clinically evident in the opposite breast, biopsy

and histological examination of the opposite breast finds 15 to 20 percent of them

cancerous (93). Normally only 0.5 percent

of these women will develop clinical

evidence of cancer in the opposite breast.

The scope for biased trends in incidence

which are due to either more complete

registration or the identification of cancer

which would not cause a serious disease is

probably large but unknowable with current procedures.

INCIDENCE AND MORTALITY TREND ANALYSIS

The magnitude and rate of change in incidence and mortality at any particular cancer site

are seldom equal. Highly fatal cancers are the

exception. In fact, comparable incidence and

mortality rates are seen for pancreatic and lung

cancers which have the poorest survival rates of

the leading cancer sites. The same does not hold

true for cancers of the endometrium, breast, or

bladder, for which survival rates are much

higher and improved over the recent past.

Major problems confront analysis of existing

U.S. cancer incidence data, while such problems

are less severe for mortality data. Incidence data

representative of the U.S. population were collected at only three points in time over a period

of more than 30 years before 1973. During that

time there were changes in survey methods, definitions of disease, diagnostic patterns, classification of disease, and in the rules for assigning

cause of death, as well as improvements in access to medical care. All of these factors may

have affected registered incidence. The more recent SEER data, while collected according to the

same basic procedures since the program’s inception, may reflect different degrees of ascertainment in startup years as compared with subsequent years. More importantly, the program

has been operating for too short a time for

trends which are real but small in magnitude to

emerge. Comparing SEER data with information from one or more of the earlier surveys

raises questions about whether data from such

different sources can be analyzed together with

sufficient validity. Despite these drawbacks,

data from the national cancer surveys and SEER

have been analyzed for trends, and provide

some useful indicators, though authors of the

analyses acknowledge inherent problems.

Devesa and Silverman (84) analyzed incidence data from the national cancer surveys

when TNCS was completed, along with mortality data for corresponding years. They reported

that between the two survey points, 1947 and

1970, the “overall age-adjusted incidence rate

for all sites combined decreased 3.9 percent.”

This summary figure is the result of ups and
Ch. 2–Cancer incidence and Mortality ● 43

downs in race-sex-site groups, including an

overall striking decrease for women and an

overall increase for men. Lung cancer was by far

the most active site, increasing more than 350

percent between FNCS, when it ranked eighth in

incidence as a primary site, and TNCS, when it

took first place. Uterine cancer, which had the

highest incidence rate in FNCS, had decreased

40 percent. Even more dramatic was the overall

72 percent decrease in stomach cancer by the

time of TNCS. Incidence trends for the most frequent sites and for all sites combined, as reported by Devesa and Silverman are displayed

in figures 2 and 3.

Devesa and Silverman believe that some of

the apparent changes may be artifactual, notably part of the dramatic increase in cancers of

the lung and prostate in nonwhite males. In addition, the lower rates for nonwhites in the

earlier periods may reflect underdiagnosis.

However, they conclude (84):

Changes are likely to have occurred in the

prevalence of carcinogenic agents either in the

general or personal environment, since the shifts

in trends, especially when considered by race

and sex, are greater than those that could be explained by the problems discussed earlier.

Doll and Peto (93) conclude that the most reliable estimates of trends in cancer incidence are

probably those derived by direct comparison of

SNCS and TNCS, though even in this comparison substantial artifacts are possible. Figures 4

and 5 display the age-standardized male and

female incidence data from SNCS and TNCS,

respectively. Figures 6 and 7 display age-standardized mortality for the period 1955 through

1975. The important changes are increases in

lung cancers and melanomas, a decrease in

stomach cancers for both sexes, increasing rates

of prostate, bladder, and kidney cancers in

males, and a sharp decrease in cervical cancer in

women.

Pollack and Horm (296) presented the first

analysis of cancer incidence rates from SEER

data. The paper, according to the authors, had

three objectives:

1. to assess the comparability of the cancer

incidence rates across the total SEER program over the period 1973-76;

2. to assess the validity of use of TNCS incidence rates for 1969-71 and SEER rates

for 1973-76 to analyze incidence trends

over the period 1969-76; and

3. to present trends in cancer incidence and

mortality for 1969-76, where data are sufficiently comparable, for some of the major forms of cancer and to summarize

these trends by use of a convenient set of

measures.

For whites, rates for all SEER areas combined,

for individual cancer sites and all cancer sites

combined were found to be “reasonably comparable. ” However, rates for blacks over the 4-

year period are not comparable, and therefore

analysis of incidence data was carried out for

whites only; mortality data were analyzed for

whites and blacks. The authors concluded, regarding the second stated purpose, that “the use

of incidence rates for TNCS areas for 1969-71

and for SEER areas for 1973-76 appears to provide a good approximation to trends over that

total time period for the white population”

(296). Pollack (295) reached the same conclusion after comparing Connecticut tumor registry data, the data from the three national cancer

surveys and the SEER program.

The authors (296) calculated the average annual percent change in incidence at each site and

all sites combined for each sex (see table 7).

However, they caution that “it can be misleading to focus on the picture for all sites” because these overall figures are affected by many

dynamic rates for different sites. For all sites

combined, the incidence rate increased an average of 1.3 percent/yr for white males, and 2.0

percent/yr for white females. Mortality rates

for all sites combined increased an average of

0.9 and 0.2 percent/yr for white males and

white females, respectively. Mortality rates for

blacks increased an average of 2.1 and 0.6 percent/yr for males and females, respectively.
Figure 2.—Age-Adjusted Cancer Incidence Trends Among Males for All Sites

Combined Showing the Most Frequent Sites

400

300

100

0

400

300

100

I

!—

White male incidence trends

Lung

Prostate

Intestines

Rectum

Bladder

All other

sites

1940 1950

Year

1960 1970

I

Nonwhite male

Lung

Prostate

ntestines

Rectum

Stomach

All other

sites

incidence trends

o

1940 1950 1960 1970

Year

SOURCE From Devesa and Silverman (84)
Ch. 2–Cancer Incidence and Mortality ● 45

Figure 3.—Age-Adjusted Cancer Incidence Trends Among Females for All Sites -- -— . . . .

400 I Combined Showing the Most Frequent Sites

White female incidence trends

300

0

0

0-

0

0

z

: 200

z

K

Breast

Uterus

Intestines

Cervix

Corpus

Rectum

Lung 100

All other

sites

o

400

1940 1950 1960 1970

Year

Nonwhite female incidence trends

Breast

Cervix

Corpus Uterus

Rectum

100 Lung

Intestines

All other

sites

o

SOURCE From Devesa and Silverman (84)

1940 1950 1960 1970

Year
46 ● Technologies for Determining Cancer Risks From the Environment

70C

60C

5oc

400

300

200

100

0

Mouth,

esophagus,

pharynx,

and larynx

.

Figure 4.—Site-Specific Cancer Incidence Rates per Million Males, All Agesa

m

.iver,

d’ Incidence

‘:~~::derl ‘one 

LA

I “adder 

L

I ‘rosta’e@I ‘eukemia ~!%~liall

11

Iucts I I I I I

sites I

Lung Intestines Pancreas Melanoma Kidney Brain and Hod~kin’s Other and

(including central dise&e unspecified solid,

rectum) nervous except

system skin

a Age.standardized to 1950 U.S. Census population, assuming 90 percent of the population is white.

SOURCE: Doll and Peto (93).
Ch, 2–Cancer Incidence and Mortality ● 47

700

600

500

400

300

200

100

0

esophagus,

pharynx,

and larynx

Figure 5.—Site-Specific Cancer Incidence Rates per Million Females, All Agesa

Q

Incidence

1

Key SNCS, 1947/8

TNCS, 1969-71

Breast I

Kidney I I

Endometrium Brain and I

Hodgkin’s I

Other

L,”=, ,

I

““0, ”

~allhladder I and other central disease and unspec.

L----- -

and

bile ducts I ‘terus F::s I I

ified solid,

except skin

Lu;g Intestines Panc!reas Mela;oma Blabder Cervi~ uteri Ovary Leukemia Other

(including reticulorectum) endothel ial

sites

a Age.~tandardlzed to 1950 U.S Census population, assuming 90 percent of the population IS white

SOURCE Doll and Peto (93)
48 ● Technologies for Determining Cancer Risks From the Environment

Figure 6.--Site-Specific Cancer Mortality Rates per Million Males at Agesa O-64 Years:

1953-57; 1963=67; and 1973-77

30,00C

25,00C

20,000

15,000

10,000

6000

2000

0 dlMouth,

esophagus,

pharynx

and.larynx

d’ Mortality c!!!!!! 1953-7

Key 1963-7

1973-7

Stomach ] Liver, I Bone Skin Hodgkin’s [ Other anc

gallbladder

and bile

ducts

I I centra l I disease I (chiefly)

I I

nervous I Iunspecified

system sites

Lung Intestines Pancreas Bladder Prostate Leukemia Other

(including reticulorectum) endothel ial

a Age.standardized to the 197’O U.S. ceIISUS population. sites

SOURCE: Doll and Peto (33)
Ch. 2–Cancer Incidence and Mortality ● 49

Figure 7.—Site-Specific Cancer Mortality Rates per Million Females at Ages’ O-64 Years:

1953-57; 1963”67; and 1973”77

20,000

15,000 —

10,000 —

6000

2000

0 1IILi

Mouth,

esophagus,

pharynx

and larynx

Lung

Stem: h

T

bill

Liver,

gallbladder

and bile

ducts

Intestines

(including

rectum)

Pancreas Skin

E!!!!! 1953-7

Key 1963-7

1973-7

Breast I I

Kidney E Brain and Hodgkin’s Other and

a central disease (chiefly

u nervous unspecified

system sites)

Bla~der Cervix ’uteri Ov’ary Leukemia Other

reticu loendothel ial

sites

a AQe.~tandardlzed to the 1970 U S Census population

SOURCE Doll and Peto (93)
50 ● Technologies for Determining Cancer Risks From the Environment

Table 7.—Age.Adjusteda Cancer Incidence Rates per 100,000 Population for Selected Sites by Sex and Year,

and Average Annual Percent Change, TNCS Areas 1969-71 and SEER Areas 1973-76: Whites

Incidence rate/100,000 population 95 ”/0

Average annual

Site Sex

confidence

1969 1970 1971 1973 1974 1975 1976 percent change interval

Ail sites . . . . . . . . . . . . . . . . .,

Stomach . . . . . . . . . . . . . . . . .

Colon excluding rectum. . . . . .

Rectum . . . . . . . . . . . . . . . . . . .

Pancreas . . . . . . . . . . . . . . . . . .

Lung. . . . . . . . . . . . . . . . . . . . . .

Melanoma . . . . . . . . . . . . . . . . .

Breast b 

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

Cervix. . . . . . . . . . . . . . . . . . . . .

Corpus–uterus NOSC 

. . . . . . .

Ovary . . . . . . . . . . . . . . . . . . . . .

Prostate gland . . . . . . . . . . . . .

Bladder . . . . . . . . . . . . . . . . . . .

Kidney . . . . . . . . . . . . . . . . . . . .

Leukemia. . . . . . . . . . . . . . . . . .

M

F

M

F

M

F

M

F

M

F

M

F

M

F

F

F

M

M

F

M

F

M

F

346.6

271.5

15.4

7.1

34.5

30.6

17.5

11.1

12.1

7.5

70.6

13.3

4.4

4.1

73.9

16.0

22.6

14.9

59.0

23.8

6.3

9.0

4.3

13.2

8.0

343.7

268.6

14.1

7.0

33.2

28.9

17.8

10.6

12.1

7.3

71.5

14.4

4.7

4.2

76.1

14.5

22.7

14.2

57.4

23.3

5.9

8.7

4.0

13.6

7.6

337.2

270.9

13.4

6.3

32.4

28.6

18.1

10.6

12.3

7.0

70.0

15.5

4.7

4.8

75.1

14.3

24.6

13.6

56.7

23.4

6.3

8.2

3.8

12.2

7.2

355.5

287.3

13.8

6.1

34.2

29.7

18.8

11.3

12.7

7.5

72.3

17.7

5.8

5.1

81.0

12.6

29.0

14.2

61.0

25.5

6.1

9.4

4.4

13.2

7.8

a1g70 U.S. population was used as standard.

blg74 and 1975 were not included in the computation of trend for breast cancer.

cNot otherwise specified.

SOURCE: Pollack and Horm, 1980.

Schneiderman (320) also reported incidence

trends from TNCS/SEER data, and his estimates of site-specific and overall change are

similar to those of Pollack and Horm. The Toxic

Substances Strategy Committee (TSSC) (345)

stated that “even after correcting for age, both

mortality (death) rates and incidence (new

cases) of cancer are increasing, ” based on

Schneiderman’s analysis. However, TSSC was

cautious about drawing firm conclusions about

the magnitude of any increase because of the

problems and uncertainties inherent in the data

and the comparison of data sets.

Doll and Peto (93) consider the TNCS/SEER

comparison “completely unreliable. ” These

authors compared incidence from the SNCS/

365.3

305.2

13.1

5.9

37.3

30.1

19.3

11.2

11.2

8.0

74.5

20.0

6.3

5.5

92.5

11.5

31.1

14.9

62.1

27.1

6.9

9.1

4.1

13.4

7.5

--- . -- . . . - --- . -- 365.8

301.8

12.7

5.4

35.5

30.6

18.3

12.0

12.5

7.2

76.4

21.8

6.4

6.0

86.2

10.7

32.4

14.2

64.8

25.8

6.9

9.0

4.0

12.5

7.3

374.0

301.2

12.6

5.6

36.9

31.4

19.4

11.4

11.5

8.0

77.8

23.7

6.8

6.1

83.5

10.6

31.2

13.6

68.6

26.4

7.3

9.6

4.8

13.1

7.1

1.3

2.0

– 2.3

– 3.7

1,5

0.7

1.3

1.2

– 0.5

0.9

8.6

6.8

6.2

1.8

– 5.9

5.9

– 0.4

2.3

2.3

2.5

1.2

1.3

– 0.2

– l o

0.74

1.28

– 3.34

– 4.70

0.29

– 0.22

0.60

0.18

– 1.96

– 0.61

0.87

8.06

5.75

5.32

1.17

– 6.67

4.48

– 1.61

1.27

1.31

1.01

– 0.20

– 1.09

– 1.51

– 2.14

1.86

2.72

– 1.26

– 2.70

2.71

1.62

.2.00

.2.22

0.96

2.41

1.93

!3.14

“7.85

7.08

2,43

– !i.13

7.32

().81

3.33

3.29

3.99

2.60

3.69

1.11

0.14

TNCS/SEER series with registered incidence

from Connecticut and upstate New York. They

also looked at U.S. mortality for the concurrent

period, and found that the TNCS/SEER portion

yielded “fantastic and irregular variations in incidence . . . ten times greater than could

plausibly be attributed to chance, and a hundred

times greater than the corresponding annual

changes in mortality over the past few decades. ”

Morgan (242) and Rothman (314) also have

challenged the validity of analyzing incidence

trends using a TNCS/SEER comparison. Further, they do not feel there is adequate evidence

t. support claims that incidence is rising. Resolving the differences of opinion concerning

trends is not possible at this time.
Ch 2—Cancer Incidence and Mortality ● 51

TRENDS IN SITE-SPECIFIC CANCER RATES

After allowing for all the biases and difficulties in interpretation, it is refreshing that

some conclusions can be drawn about trends in

cancer rates at specific body sites. As discussed

earlier in this chapter, mortality rates in this

country are more reliable than the available incidence rates, thus this discussion of site-specific

trends relies more heavily on mortality than incidence rates.

Although it is uncertain how far back cancer

death certification rates can be considered reliable, 1950 is a sensible starting point for discussing modern trends, In 1950, there were new

rules for coding death certificates and a new

census. The classification of cancers had just

begun to be based on a reasonably modern International Classification of Diseases (the sixth

ICD). For example, Hodgkins’ disease was classified as a neoplasm rather than an infectious

disease, the lymphomas were listed separately,

and the important distinction between cancer

of the cervix and other uterine cancers had recently begun. Moreover, by 1950, fairly modern

standards of diagnostic radiology already existed, and nontoxic anesthesia and the chemotherapy of infectious diseases had just developed, allowing for successful operations against

cancer (93).

Trends in mortality rates from all malignancies are depicted in figure 8, Mortality rates and

rate of charge differ between whites and nonwhites and between males and females. Consideration of such overall rates are not so informative as consideration of rates at particular

sites, which follows. The discussions draw on

data presented in tables 8 and 9 which display

cancer mortality rates for people under 65 and

over 65, respectively and figures 9 through 17

which present age-standardized cancer mortality trends for the years 1950-78.

Figure 8.—Mortality Rates for All Malignancies

(ICD 8: 140-209) per 100,000, Age-Standardized to .

U.S. 1970 Population;: 1950-77

1950 1955 1960 1965 1970 1975 1980

SOURCE” Office of Technology Assessment

Respiratory cancer sites, dominated by lung

cancer, shows the most dramatic increases (see

fig. 9). Male respiratory cancer rates appear to

have been rising for at least half a century.

Female respiratory cancer death certification

rates started to rise 25 years ago and are now increasing rapidly. Before 1950, almost the whole

of the apparent increase in female lung cancer

and some of the apparent increase in male lung

cancer may be artifactual, due to increasingly

accurate detection during the period 1933 to
52 ● Technologies for Determining Cancer Risks From the Environment

Table 8.—U.S. Age-Standardized Cancer Death Rates for Males and Females Under 65

1953-78

Average annual rates/100 million aged under 65a

Only

Site Sex 1953-57 1958-62 1963-67 1968-72 1973-77 1978

Mouth, pharynx,

larynx, or esophagus

Remaining respiratory:

Trachea, bronchus,

or Iungc

Pleura, nasal sinuses,

and all other

Both

Stomach

Intestines (chiefly large

intestine, i.e., colon and

rectumd

)

Liver e

Gallbladder and

ductsf

Both

Pancreas

Remaining digestive (chiefly

peritoneum*

Bone

Connective and soft tissue

sarcomas

Skin (chiefly melanomah

)

Breast

Bladder i

Kidneyi

Cervix uteri

Endometrium J

Ovary

Prostate

Other genital:

Malignant

Malignant

Benign and unspecified

Brain or nerves, malignant,

or benignk

Eye

Thyroid

Leukemia

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

F

F

F

M

M

F

F

M

F

M

F

M

F

M

F

5,936

1,213

18,275

2,714

6,808

3,293

8,954

9,014

1,203

1,520

3,984

2,210

465

414

936

656

355

276

1,325

916

138

15,880

2,066

760

2,012

1,008

7,550

4,218

5,692

2,785

854

356

835

4,908

3,675

127

116

236

340

4,754

3,562

6,485

1,478

21,290

3,378

5,539

2,717

8,739

8,576

1,396

1,425

4,336

2,363

427

370

795

552

419

338

1,410

935

127

16,158

1,919

676

2,051

1,006

6,651

3,282

5,736

2,602

852

326

444

4,822

3,663

120

106

207

304

4,843

3,477

6,858

1,700

25,390

4,734

4,478

2,216

8,624

7,977

1,362

1,219

4,536

2,459

404

330

747

483

492

373

1,659

1,040

121

17,053

1,810

655

2,134

991

5,673

2,650

5,680

2,549

837

291

302

4,831

3,653

102

100

186

255

4,705

3,338

— --- — -- — ---

7,059

2,000

28,799

7,133

475

215

29,274

7,348

3,753

1,815

8,521

7,486

807

354

535

712

1,342

1,066

4,464

2,482

351

265

680

444

516

421

1,547

1,022

130

17,358

1,658

547

2,206

1,018

4,423

2,193

5,621

2,555

811

274

173

4,693

3,520

92

82

182

210

4,344

3,049

7,123

2,143

30,911

9,803

447

192

31,358

9,995

3,270

1,551

8,298

7,130

795

347

488

644

1,283

991

4,267

2,598

283

212

600

380

464

414

1,828

1,086

123

17,260

1,538

500

2,236

1,016

3,365

1,966

5,304

2,612

729

246

95

4,475

3,364

77

66

153

177

4,036

2,753

7,200

2,111

32,080

11,598

408

178

32,488

11 ,776

2,983

1,403

8,276

6,807

789

383

487

625

1,277

1,008

4,148

2,618

256

193

575

360

473

426

1,996

1,161

110

17,229

1,386

455

2,300

1,011

2,911

1,815

5,042

2,590

540

224

53

4,293

3,246

70

58

146

181

3,845

2,622
Table 8.– U.S. Age-Standardized Cancer Death Rates for Males and Females Under 65,1953-78 (Continued)

Average annual rates/100 million aged under 65a

Only

Site Sex 1953-57 1958-62 1963-67 1968-72 1973-77 1978

Hodgkin’s disease M 1,775 1,770 1,770 1,573 1,065 830

F 992 999 1,025 918 620 486

All other Iymphomasl M 3,603 3,862 4,070 4,429 4,254 4,267

F 2,260 2,543 2,720 2,884 2,875 2,876

Remainder (chieflym M 5,935 5,775 6,490 5,805 6,029 6,304

deaths where the anatomic F 5,244 4,800 4,868 4,669 4,734 4,613

site or origin of the cancerous cells was not recorded)

a There are currentiy about 100 mllllon people of each sex aged under 65, so the cited rates are roughly slmllar to the actual numbers of such deaths.

b These are the cancers which are strongly affected both by alcohol and by all forms of tobacco.

c Lung (tncluding trachea and bronchus) cancer rates are affected more strongly by cigarette than by pipe smoking, and the Increases In respiratory cancer among people aged under 65 during the past quarter century can be chiefly ascribed to prior widespread adoption of cigarette smoking.

d Cancer of the Intestines may arise In the small lntestfne, (n the ascending, transverse, descending or slgmold colon, or in the rectum, U S. mortallty data do not seem

to be sufflc!ently precise to allow unbiased examination of the trends In any of these separate parts, not even merely “colon” and “rectum”.

e Lwer speclfled as primary, Includlng the bile ducts Inside the I(ver.

f Gallbladder, Includlng the bile ducts outside the Ilver

g Mesentery, peritoneum and unspeclfted dlgestlve sites (the latter comprtslng the mmority In 1948, when separate totals were last publmhed).

h In middle age there are now so few deaths from nonmelanoma skin cancers that the data for “total skin” represent the melanoma death rates reasonably accurately,

but In old age the continuing decrease In the death rates from nonmelanoma sktn cancers still dilutes the progressive Increase In melanoma death rates.

I “Other urinary organs” (ureter and urethra, where cancers are rare) were Included with “bladder” up to 1967, and were then transferred to “kidney” from 1968

onwards

J Endometrlum, Includlng all cancers of unspecified parts of the uterus

k The dlstlnctlon between “mall gnant ” and “berrtgn ” IS less clear-cut for brain tumors than for most other neoplasms, and so the most meaningful analySIS Seem S to

be of all fatal tumors of the central nervous system, Irrespective of histology. However, even here, large biases are possible, for In old age symptoms due to brain

tumors may be mlsd!agnosed as due to sen!llty or vascular disease Such errors are, of course, less Ilkely In middle age, which may account for the marked upward

trend In bratn tumor death cerfjfjcaflon rates In old age being entirely absent In middle age.

I There IS considerable diagnostic uncertainty between Iymphosarcoma, reticulum cell sarcoma and various other Iymphomas, so we have not attempted to examine

them separately Myeloma IS also Included since data on myeloma were publlshed separately only from 1968

rT In years when any d Istlnct Ion between them can be made from the U.S Government publ Icat Ions, the “unspeclfled ?.Ite” death certificates greatly outnumber the

“speclffed sites” among those remalnmg cancers, although the dlstlnctlon between them seems surprisingly erratic (e g., comparing 1957 with 1958)

SOURCE Doll and Peto (93)

1950, but some of the pre-1950 male increase

and virtually all of the more recent increases in

both sexes are real and largely or wholly caused

by the delayed effects of the adoption of the

habit of cigarette smoking decades ago.

The long delay between cause and full effect

arises because the exact age at which smoking

began during the late teens or early twenties is a

surprisingly important determinant of lung cancer risks in middle or old age. The dependence

of lung cancer risks in old age on cigarette

smoking habits in early adult life means that

lung cancer rates among people in their sixties

during the 1970’s are strongly influenced by the

smoking habits of teenagers and people in their

early twenties back about 1930 (93).

An encouraging sign is the decrease in lung

cancer mortality rates among white men in all

age groups under age 50 (fig. 10). This decrease

is associated with both decreased smoking rates

among men and decreased tar yield of new cigarettes. Smoking rates among women rose at

least throughout the 1960’s. (Trends during the

1970’s are not clear. ) As a result, all age-specific

female rates are still rising, except those at ages

30 through 39, which apparently have stopped

rising. These increasing rates suggest that by the

turn of the century, lung cancer rates among

middle-aged women may no longer be rising,

but rates among older women will probably

continue increasing because of higher smoking

rates during their early adult lives (93).

Mouth, pharynx, larynx, and esophagus

(figure 11) are the sites at which cancers can be

caused by alcohol and by tobacco, including the

pipe tobacco which men have used since the last

century. The combination of both alcohol and

tobacco exposure seems to cause an increase in

the risk of these cancers which greatly exceeds

the sum of the two separate risks. Mortality

rates at these sites have remained relatively constant since 1950 for whites, but nonwhite males
54 ● Technologies for Determining Cancer Risks From the Environment

Table 9.—U.S. Age-Standardized Cancer Death Rates for Males and Females Over 65,1953-78

Average annual rates/10 million aged 65 or overa

Only

Site Sex 1953-57 1958-62 1963-67 1968-72 1973-77 1978

Mouth, pharynx,

larynx, or esophagus

Remaining respiratory:

Trachea, bronchus

or Iungc

Pleura, nasal sinuses,

and all other

Both

Stomach

Intestines (chiefly large

intestine, i.e. colon and

rectumd):

Liver e

Gallbladder and

ducts

Both

Pancreas

Remaining digestive (chiefly

peritoneum

Bone

Connective and soft tissue

sarcomas

Skin (chiefly melanomah

)

Breast

Bladderi

Kidneyj

Cervix uteri

Endometriumj

Ovary

Prostate

Other genital:

Malignant

Malignant

Benign and unspecified

Brain or nerves, malignant

or benignk

Eye

Thyroid

Leukemia

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

F

F

F

M

M

F

F

M

F

M

F

M

F

M

F

8,027

1,786

—

—

—

—

14,277

2,937

14,368

7,547

17,916

15,502

7,580

1,654

—

—

19,016

2,981

11,827

5,930

17,749

14,672

7,214

1,551

24,823

3,442

9,552

4,635

17,761

14,024

1,921

2,651

5,816

3,842

729

649

837

468

228

156

1,867

1,118

201

11,356

5,416

2,258

1,735

1,047

3,127

4,068

3,195

19,300

435

645

240

935

596

131

106

276

524

3,924

2,273

2,106

2,561

6,426

4,074

668

610

617

359

273

184

1,739

961

166

10,633

5,496

2,042

1,969

1,066

2,884

3,512

3,344

18,584

359

604

147

1,068

692

123

91

251

450

4,512

2,474

2,208

2,357

6,899

4,226

628

540

521

308

323

209

1,679

863

175

10,351

5,501

1,876

2,166

1,105

2,513

3,175

3,460

18,488

320

545

115

1,375

857

106

79

234

417

4,855

2,612

7,324

1,643

31,539

4,692

483

205

32,022

4,897

7,708

3,667

17,958

13,497

926

364

1,267

1,749

2,193

2,113

7,090

4,390

500

431

502

286

357

243

1,448

780

192

10,603

5,626

1,673

2,488

1,160

2,021

2,861

3,680

18,591

295

514

72

1,731

1,187

112

79

232

372

5,015

2,704

7,478

1,787

37,424

6,550

492

195

37,916

6,745

6,519

3,047

18,265

13,256

957

376

1,193

1,479

2,150

1,855

7,169

4,463

483

365

465

261

353

244

1,527

789

188

11,087

5,781

1,615

2,543

1,222

1,642

2,662

3,743

19,465

252

495

51

2,163

1,522

99

70

210

338

5,053

2,609

7,487

1,933

40,888

8,296

468

203

41,:356

8,499

5,892

2,870

18,839

13,437

1,067

395

1,192

1,459

2,259

1,854

7,247

4,637

417

317

436

244

355

273

1,608

840

181

11 ,070

5,732

1,623

2,670

1,252

1,403

2,593

3,796

20,392

224

470

39

2,581

1,862

102

64

217

310

5,142

2,627
Table 9.—U.S. Age-Standardized Cancer Death Rates for Males and Females Over 65,1953-78 (Continued)

Average annual rates/10 million aged 65 or overa

Only

Site Sex 1953-57 1958-62 1963-67 1968-72 1973-77 1978

Hodgkin’s disease M 626 600 626 592 468 384

F 388 374 397 385 296 261

All other Iymphomas1 M 2,701 3,303 3,900 5,126 5,787 6,266

F 1,849 2,227 2,634 3,470 3,894 4,184

Remainder (chieflym M 8,637 7,945 8,650 8,198 9,248 9,666

deaths where the anatomic F 7,324 6,341 6,294 6,038 6,354 6,502

site or origin of the cancerous cells was not recorded)

a There are currently about 10 mllllon Americans of each sex aged 65 or over, so the cited values are roughly similar In magnitude to the actual numbers of such deaths.

b These are the cancers which are strongly affected both by alcohol and by all forms of tobacco.

c Lung (including trachea and bronchus) cancer rates are affected more strongly by cigarette than by pipe smoking, and the Increases In respiratory cancer among People aged under 65 during the past quarter century can be chiefly ascribed to prior widespread adoption of cigarette smoking.

d Cancer of the intestines may arise In the small Intestine, in the ascending, transverse, descending or sigmoid colon, or in the rectum. U.S. mortallty data do not seem

to be sufficiently precise to allow unbiased examination of the trends in any of these separate parts, not even merely “colon” and “rectum”.

e Liver specified as primary, Including the bile ducts inside the Iwer.

f Gallbladder, lncludlng the bile ducts outside the liver.

g Mesentery, peritoneum and unspecified digestive sites (the latter comprising the minority in 1948, when separate totals were last published).

h In middle age there are now so few deaths from nonmelanoma skin cancers that the data for “total skin” represent the melanoma death rates reasonably accurately,

but tn old age the continuing decrease in the death rates from nonmelanoma skin cancers still dilutes the progressive increase in melanoma death rates.

i “Other urinary organs” (ureter and urethra, where cancers are rare) were included with “bladder” up to 1967, and were then transferred to “kidney” from 1968

onwards.

I Endometrium, Including all cancers of unspeclfted parts of the uterus.

k The distinction between “mall gnant” and “benign” IS less clear-cut for brain tumors than for most other neoplasms, and so the most meaningful analys!s seems to

be of all fatal tumors of the central nervous system, irrespective of histology. However, even here, large biases are possible, for In old age symptoms due to brain

tumors may be misdiagnosed as due to senlllty or vascular disease. Such errors are, of course, less likely in middle age, which may account for the marked upward

trend In brain tumor death certlficatjorr rates In old age being entirely absent in middle age.

I There IS considerable diagnostic uncertainty between Iymphosarcoma, reticulum cell sarcoma and various other Iymphomas, so we have not attempted to examine

them separately Myeloma IS also included since data on myeloma were publlshed separately only from 1968

mln years when any distinction between them can be made from the U S. Government publications, the “unspecified site” death certificates greatly outnumber the

“speclfled sites” among those remaining cancers, although the dlstmctton between them seems surprisingly erratic (e.g., comparing 1957 with 1958).

SOURCE: Doll and Peto (93)

experienced a large increase and nonwhite females a smaller, but notable, increase.

Stomach cancer (fig. 12) is now decreasing

throughout the developed world. The enormously encouraging feature of the U.S. stomach

cancer trends is that they are continuing downwards throughout middle age, which strongly

suggests that as those people and subsequent

cohorts age, they will have lower rates in old

age than do older people today. The United

States, which used to have very high stomach

cancer rates, now has incidence rates which are

among the lowest recorded in any country in the

world.

No single explanation adequately explains the

decrease, but several factors have been suggested as contributors: modern techniques of

food preparation and storage, increased consumption of green vegetables, fruits, and antioxidant (as food preservatives), and increased

milk intake (237). These associations are difficult to study epidemiologically because individuals may alter their diet throughout life

and it is difficult to reconstruct past consumption patterns.

Intestinal cancer (fig. 13) may either be of a

specified or of an unspecified part of the intestine. In 1958, about two-thirds of male intestinal cancer deaths were certified as being of

some specific intestinal site (small intestine,

ascending colon, transverse colon, descending

colon, sigmoid colon, or rectum), and one-third

were of an unspecified intestinal site, while by

1977 the converse was true. Overall there was

little change in total male intestinal cancer mortality during this period. Clearly, although the

male death certification rates for each specific

intestinal site have been approximately halved,

these decreases cannot be accepted as real, since

the “unspecified site” rates have doubled.

Moreover, it has been traditional to compile

separate data for the “rectum,” the last foot or
56 ● Technologies for Determining Cancer Risks From the Environment

Figure 9.–Respiratory Cancer (lCD 8: 160-163)

Mortality Rates per 100,000, Age-Standardized to

U.S. 1970 Population: 1950-77

1950 1955 1960 1965 1970 1975 1980

SOURCE Office of Technology Assessment

so of the large intestine, and to describe the remainder, including unspecified intestinal sites,

as “colon.” Inspection of the data gives the

misleading impression that rectal cancer rates

are decreasing and colon cancer rates are increasing, while in fact the decreases in the death

certification rates for rectum are if anything

slightly less extreme than for other specified

parts of the intestines. In view of the fact that

half of all fatal cancers diagnosed in hospital as

“rectum” in TNCS, were eventually certified as

“colon,” the most plausible interpretation of the

data is that there have been no material trends

in either colon or rectal cancer mortality during

the past 25 years among males, although both

the incidence and mortality data do suggest a

slight decrease in onset rates below 65 years of

Figure 10.—Trends Since 1950 in U.S. Male

‘Lung Cancer Mortality at Young Ages

1950 1955 1960 1965 1970 1975 1980

Yea r

SOURCE: Doll and Peto (93).

age (93). Similar difficulties of classification affect data for females, and when all intestinal

sites are combined, total female intestinal cancer

death rates appear to be decreasing steadily

since 1950.

Liver cancer currently accounts for 0.8 percent of cancer deaths among Americans under

65 and no statistically significant trends in liver

cancer mortality are evident during the past decade. Incidence trends show a decrease in liver

cancer, which is probably artifactual and due to

improving differential diagnosis between primary liver cancer and cancers which have metastasized from other sites to the liver. This
Ch. 2—Cancer Incidence and Mortality ● 57

Figure 11 .—Combined Mouth, Pharynx, Larynx, and

Esophagus Cancer(ICD8:140-150~ 161) Mortality

Rates per 100,000, Age-Standardized to U.S. 1970

27

24

21

19

16

13

10

7

4

2.5

.

Population: 1950-77

1950 1955 1960 1965 1970 1975 1980

SOURCE Off Ice of Technology Assessment

decrease may be somewhat surprising in that the

liver is intimately exposed to much of what is ingested, and it is composed of cells which are

capable of rapid proliferation when necessary.

Moreover, many of the chemicals that have thus

far been found to be carcinogenic in animal

feeding experiments cause liver cancer in

animals.

Gallbladder and bile duct cancers are unfortunately not reported separately either in mortality data or in the data from SNCS, though

they are in TNCS. Cancers at these sites have

different causes, however. Gallstones are a risk

factor for gallbladder but not bile duct cancer.

According to TNCS data, females develop

Figure 12.—Stomach Cancer (ICD 8: 151) Mortality

Rates per 100,000, Age-Standardized to U.S.

1970 Population: 1950-77

1950 1955 1960 1965 1970 1975 1980

SOURCE Off Ice of Technology Assessment

Figure 13.—Combined Small Intestine, Colon, and

Rectum Cancer (ICD 8: 152-154) Mortality Rates per

100,000, Age-Standardized to U.S. 1970 Population:

1950-77

n I I I I 1

1950 1955 1960 1965 1970 1975 1980

SOURCE Office of Technology Assessment
58 . Technologies for Determining Cancer Risks From the Environment

cancer of the gallbladder more frequently than

cancer of the bile ducts, while for males the ratio

is the inverse.

Decreases have occurred and are continuing

to occur in the aggregate of the two cancers, and

these decreases are larger among females than

among males. The figures suggest that it is

cancer of the gallbladder that is chiefly decreasing, rather than cancer of the bile ducts.

Pancreatic cancer (fig. 14) is now decreasing

in males at ages under 65, the decreases in early

middle age being particularly rapid. This

decrease is especially encouraging because it

comes after decades of gradually but steadily increasing rates. Pancreatic cancer is so uniformly

fatal that treatment cannot have affected these

trends. If the correlation of smoking with pancreatic cancer represents a cause-and-effect relationship, one might expect the ratio of rates

among smokers to nonsmokers to be increasing,

as has been the case in recent years for lung

cancer. If the association is causal, then among

middle-aged nonsmokers the trend in pancreatic

cancer mortality must be even more steeply

downwards than these national data suggest.

Bone cancer death certification (and incidence) have shown apparent decreases, which

Figure 14.—Pancreas Cancer (ICD 8: 157) Mortality

Rates per 100,000, Age-Standardized to U.S.

1970 Population: 1950.77

15

10

5

0

1950 1955 1960 1965 1970 1975 1980

SOURCE. Off Ice of Technology Assessment

may be due largely to the progressive elimination of misdiagnosed secondaries (93). However, it is now impossible to determine whether

or not actual decreases have occurred.

Skin cancer mortality increases from 1950

through 1978 are a result of an increasing death

rate from melanomas, offset partially by a

decreasing death rate from other skin tumors.

The increases are most rapid in middle age, so

the rates in old age will probably increase even

more rapidly in future decades than is now the

case. The causes of melanoma are not wellunderstood; exposure to sunlight seems to be involved, and people with a genetic deficiency in

their ability to repair the damage done to DNA

by sunlight are at extraordinarily high risk of

melanoma (310). However, people whose work

involves regular outdoor exposure seem paradoxically to be at lower risk of melanoma than

otherwise similar people who work indoors

(93), perhaps because a permanent suntan is

protective. This may be at least in part a result

of self-selection for outdoor work, or perhaps

the conditions that maximize risk are those

which involve sudden exposure of untanned

skin to sunlight. It is possible that the

worldwide increases in melanoma are due merely to some change in the pattern of human exposure to sunlight, e.g., changes in clothing and

increases in sunbathing, particularly since the

chief increases seem to be in melanoma of the

trunk and legs rather than face (93). Alternatively since melanocytes are subject to hormonal influences, it could be that other causes

are also important.

Breast cancer (fig. 15) incidence and mortality

at ages under 65 show no substantial changes,

but that overall rate conceals smaller fluctuations in mortality in particular age groups. Based on the accepted association of age at first

childbirth and breast cancer risk (219), Blot (27)

has argued that the reproductive patterns of different cohorts of American women can account

for some or all of the small fluctuations in breast

cancer death rates in particular cohorts of

women. Women who were young during the

Great Depression of the 1930’s somewhat

delayed having their children, and their breast

cancer mortality now is slightly increased.
Ch. 2–Cancer Incidence arid Mortality ● 59

Figure 15.— Breast Cancer (ICD 8: 174) Mortality

Rates per 100,000, Age-Standardized to U.S.

1970 Population: 1950-77

1950 1955 1960 1965 1970 1975 1980

SOURCE Off Ice of Technology Assessment

Women bearing children in the postwar baby

boom had their babies at earlier ages and have

now, in early middle age, substantially decreased breast cancer rates because of their early

pregnancies.

Bladder cancer death rates in both sexes are

decreasing steadily. The trend is encouraging,

since bladder cancer can be caused by occupational exposure to various carcinogens. However, the discrepancy between rising incidence

and falling mortality is more marked for bladder than for any other type of cancer except thyroid cancer (see p. 60). These diverging trends

may be partly accounted for by improved treatment, but another reason is a shift in the classification of the two types of bladder tumors: papillomas and carcinomas. Lesions that are today

considered carcinomas and included in incidence statistics, would formerly have been labeled papillomas, and not counted as such (93).

Kidney cancer death rates have been slowly

but continually increasing for 25 years in males

under age 65. Rates for females have just recently begun to rise. The mortality increases are accompanied by slight increases in incidence in

both sexes. Mutagens have been detected in the

urine of male smokers (369), and epidemiologic

studies suggest about a 40 percent excess of kidney cancer among smokers (see ch. 3, “Tobacco”). Additional evidence is needed to confirm

or refute an association of kidney cancer and

smoking. If confirmed, all or most of the upward trend in mortality from kidney cancer

could be attributed to tobacco.

Uterine cancer (fig. 16) mortality has decreased dramatically throughout the past 50

years, the combined effect of large decreases in

cervical cancer mortality and smaller decreases

in mortality from endometrial cancer. The

downward trend in cervical cancer began long

before screening for cancer of the cervix became

widespread, and is the chief reason for the large,

steady decrease in female nonrespiratory death

rates over the past 40 years. The causes of this

substantial improvement are not fully understood, although effects of improved personal

Figure 16.—Uterus Cancer (lCD 8: 180-182) Mortality

Rates per 100,000, Age-Standardized to U.S.

1970 Population: 1950-77

40l

25

20

15

10

5

1950 1955 1960 1965 1970 1975 1980

SOURCE Off Ice of Technology Assessment
hygiene may be relevant. It is not known what

effect cervical cancer screening programs have

had on cervical cancer mortality. Also, many

cervical deaths between 1933 and 1978 were certified merely as being due to “cancer of the

uterus” (with the exact site not otherwise specified). If these deaths could be transferred from

endometrium, where they now are, to cervix,

the downward trend in cervical cancer would

presumably be much steeper and that from

cancer of the endometrium much shallower,

which is supported by the trends in incidence.

Finally, an increasing percentage of American

women in middle and old age, when cancer is

most common, have already undergone hysterectomy for various reasons, thereby removing

both uterine cervix and endometrium (and,

sometimes, both ovaries) from risk. A better

statistic for these cancers might be the death rate

per uterus or per ovary and not per woman.

Prostate cancer (fig. 17) becomes increasingly

common with age, more so than for most other

cancers. Incidence rates for prostate cancer

probably are not reliable, being influenced by

Figure 17.—Prostate Cancer(lCD 8: 185) Mortality

Rates per 100,000, Age-Standardized to U.S.

1970 Population: 1950.77

40

35

30

25

20

15

0

1950 1955 1960 1965 1970 1975 1980

SOURCE. Off Ice of Technology Assessment.

poorer census data for older age groups, and

most importantly, the more thorough search for

lumps, which would not have come to clinical

attention in earlier years.

Mortality data appear to be reliable, however, and indicate a marked divergence of rates

for whites and nonwhites. The rate for whites

has remained more or less constant since ‘1950,

while the rate for nonwhites has risen steadily,

and has not leveled off. The reasons for these

patterns are not known.

Brain tumors, whether malignant, benign, or

of unspecified types are not reliably distinguishable, therefore the three types are combined to

examine trends. Under age 65, a l-percent per

year decrease in brain tumor death rates is seen.

Over 65, the opposite is true, and there is a very

rapid increase in brain cancer death rates, possibly due to a steady improvement of diagnostic

standards.

Thyroid cancer is not common, accounting

for less than 1 percent of all cancer deaths. “Thyroid cancer death rates have fallen steadily from

1950 to the present, while a large increase in incidence occurred through at least 1970. The discrepancy between incidence and mortality can

be at least partly explained by the many cases,

mostly nonfatal, induced by medical radiation

of the thyroid, head, and neck. These X-ray

practices have largely been discontinued. The

decrease in mortality may be a result of improved treatment, as well as possible real decreases in the incidence of serious cases.

Hodgkin’s disease and certain forms of leukemia are much more treatable now than a decade or two ago. This fact alone accounts for the

observed substantial downward trends in mortality, especially among younger people. The

availability of successful treatments may also

have encouraged more thorough efforts at correct diagnosis. Reliable estimation of trends in

the various completely different types of leukemia is, unfortunately, not possible from the

available data. The lack of any net trend in

either direction in leukemia mortality among

older people may represent a balance between

increasingly thorough diagnosis among elderly

patients who are dying of leukemia and slightly
Ch. 2—Cancer lncidence arid Mortality ● 61

better treatment of the disease. The incidence

data suggest that some decreases in real onset

rates for leukemia are in progress, at least

among females (93).

Myelomatosis death rates have been rising

steadily from 1968 through 1978, more so for

older than for middle-aged people, for unknown

reasons. The apparent increase may be real, but

may be largely or wholly due merely to be improved case-finding, for improved case-finding

SUMMARY

The ability to analyze cancer incidence and

mortality depends on the available data. Qualifications are attached to the reliability of both

kinds of data, more to incidence data because

they have been collected over smaller geographical regions for shorter periods of time, but certain conclusions can be drawn.

Respiratory cancer incidence and mortality

have increased dramatically in both sexes, but

the last few years have seen a decline in 1ung

cancer rates among young men, The increases

and the more encouraging decreases are associated with changes in smoking habits. The

decrease in cancer death rates for females during

the last 50 years is partly explained by dramatic

decreases in deaths from cancer of the uterine

cervix. Stomach cancer mortality has decreased

substantially in both sexes.

When cancer mortality from all nonrespiratory sites are considered together, a decrease is

seen in females since 1950 (due to decreased cermust have occurred during 1968-78 and might

be expected to have its greatest effect among the

old.

Unspecified sites account for 6 to 8 percent of

all cancers at ages below 65. The exact percentage varies irregularly from 1950. Rather surprisingly, given better diagnostic criteria in recent

years, slight increases in cancer at unspecified

sites have been seen during the past decade,

vical and stomach cancers). Male death rates

have remained about level over the same period. While stomach cancer death rates have decreased in men increases at other sites have

balanced those decreases.

A controversy is swirling around the interpretation of incidence rates. Data collected in

TNCS (1969-71) and NCI’s SEER program

(1973-78) show that overall cancer incidence increased more than 1 percent per year over that

decade. The large changes, major increases in

lung cancer and decreases in cervical and

stomach cancers, are the same as those observed

in mortality trends. However, increases seen at

other sites are not universally accepted as reflecting actual change, because of differences in

methodology between TNCS and SEER. Continuation of the SEER program may provide

data to better answer questions about cancer incidence.
3.

Factors Associated With Cancer
Contents

Associated WithVarious%actors. . ......,.108

FIGURE

Figure No. Page

18. Relative Risks of Esophageal Cancer in

Relation to the Daily Consumption of

Alcohol and Tobacco . . . . . . . . . . . . . . . . . . 75
Factors Associated With Cancer

A select committee of the World Health Organization (WHO) broadly defined environmentally caused cancers as those in which extrinsic

factors are responsible (364):

These include all environmental carcinogens

(whether identified or not) as well as “modifying

factors” that favor neoplasia of apparently intrinsic origin (e. g., hormonal imbalances, dietary deficiencies, and metabolic defects).

This overarching picture of “environment”

contrasts sharply with the more usual use of the

word “environment .“ Common usage is restricted to what is seen as the purview of the Environmental Protection Agency (EPA): air,

water, and soil.

GENETICS AND ENVIRONMENT

Environment, as used in this assessment, excludes genetic factors. Genetic makeup does,

however, play a role in determining the probability of an individual developing cancer.

Knudson (201) classifies all individuals as falling

into four groups, according to the participation

of heredity and environment in the possible

development of cancer:

1.

2.

3.

4.

genetic predisposition to cancer even in

the absence of environmental variation;

predisposition imposed by environmental

variation in the absence of genetic variation;

predisposition imposed by both genetic

and environmental factors; and

neither genetic nor environmental predisposition.

The first category represents individuals with

a genetic defect who have an extremely high

probability of developing one or more particular cancers, regardless of environmental factors.

Retinoblastoma, a malignancy of the retina, is a

The WHO committee expressed its belief that

“the majority of cancers are caused by, or their

causation modified by extrinsic factors” (364).

This view represents a general consensus among

cancer researchers, and lays the foundation for

the theory that the majority of cancers are

preventable. Individuals have gone further than

the WHO committee, and have used figures of

60 to 90 percent for the proportion of cancers

that are potentially preventable (31,115,164,

165,166,368). These and other estimates have

been erroneously cited as if they referred only to

man-caused pollution or even more narrowly,

only to manmade chemicals, in the “environment. ” In this report, “environment” is used

to describe the gamut of exposures and behaviors that are associated with cancer.

childhood cancer which develops in about 95

percent of those with the genetic predisposition.

Several other childhood tumors—neuroblastoma and Wilms’ tumor of the kidney—fall into

this category. In adults, polyposis of the colon,

an inherited condition, often leads to colon

cancer; another hereditary syndrome is characterized by high susceptibility to cancers of the

colon and endometrium, and other inherited

conditions are associated with other cancer

sites. Fortunately, these conditions are relatively rare and are involved in probably 1 to 2 percent of all cancer. Categories 2 and 4 represent

cancers which are not dependent on genetic

susceptibility.

A well-understood example of the third category is xeroderma pigmentosum, a genetic condition involving a defect in deoxyribonucleic

acid (DNA) repair mechanisms. Affected individuals exposed to ultraviolet light, a component of sunlight, develop skin tumors, as well as

other skin abnormalities and some internal

65
66 ● Technologies for Determining Cancer Risks From the Environment

tumors. However, if sunlight is avoided entirely, these individuals will not develop tumors.

Both environmental and hereditary predisposing factors must be present for clinical manifestation of the disease.

Xeroderma pigmentosum is rare, but the occurrence of many common cancers have a genetic component as well. One of potentially

large importance is an apparent relationship between genetically controlled responses to cigarette smoke carcinogens (197) and the probability of developing lung cancer.

Daughters of breast cancer patients have a

higher risk of developing breast cancer than

women without this family history, though

many other factors affect the probability of the

cancer occurring. Individuals with deeply pigmented skin have a lower risk of skin cancer induced by sunlight. (The above discussion draws

heavily on Knudson (201).)

MULTISTAGE DEVELOPMENT OF CANCER

Cancer epidemiology and experimental carcinogenesis have established that the carcinogenic process is multifactor in its causation and

multistage in its development (302).

Multifactored causality means that several

agents, environmental and genetic, may be involved in cancer occurrence. The multistep development of cancer is pictured as involving at

least two steps which must occur in sequence in

the cell that is eventually to develop into a tumor. The two steps are generally called “initiation” and “promotion,” and more general

terms are “early” and “late” events.

Some substances, “complete carcinogens, ”

function both as initiators and promoters.

Other substances are known to behave only as

either initiators or promoters.

Initiation is seen as occurring in response to

an external stimulus and produces a cell that is

“latently premalignant” (302). The initiation

event is generally thought to be a mutational

change in the cell’s genetic material, but the

SHARED RESPONSIBILITY

Attribution of the risk of cancer to specific,

single causes is the exception rather than the

rule. Genetic factors affecting individual susceptibility are frequently part of the interaction.

Of more relevance to this assessment are environmental agents which interact with each other

to produce carcinogenic effects.

change is unexpressed and causes no detectable

change in the cell’s growth pattern. Initiated

cells can remain as such for at least a large segment of the animal’s life without being removed, destroyed, or otherwise harmed in any

measurable way (116).

In laboratory experiments, exposure of an initiated cell to another substance, a promoter,

converts the cell to an “irreversible malignancy”

(302). Promoters convert only initiated cells to

tumor cells and have no lasting effect on noninitiated cells. The long latency period between exposure to carcinogens and the manifestation of

disease may represent the time necessary for the

occurrence of a promotional event.

The importance of initiation and promotion

(or early and late events in carcinogenicity) in

humans is that interference in either one might

reduce cancer’s toll. Radman and Kinsella (302)

draw attention to the possibility of identifying

substances which can inhibit the activities of

either initiators or promoters.

There is clear evidence that smoking acts

synergistically with some other factors. Synergism in this context means that the number of

cancers resulting from exposure to two agents is

greater than the sum of cancers that would be

expected from the two exposures individually.

Smoking interacts with ionizing radiation to
Ch. 3—Factors Associated With Cancer ● 67

produce cancer of the lung; and with alcohol to

produce cancer of the esophagus. One of the

best known synergisms is the interaction of

tobacco and asbestos.

Asbestos and Smoking

In 1979, the Surgeon General stated (286):

Asbestos provides one of the most dramatic

examples of adverse health effects resulting from

interaction between the smoking of tobacco

products and an agent used in the workplace.

Exposure to asbestos is one of the most extensively studied occupational health hazards, and

one which continues to attract the efforts of epidemiologists, in part because of its interaction

with smoking, Indisputable evidence links asbestos to lung cancers and to rare cancer types,

mesotheliomas of the pleura and the peritoneum. Smokers exposed to asbestos, especially

those exposed at high levels, have a much greater probability of developing lung cancers than

either smokers not exposed to asbestos, or nonsmokers exposed to asbestos. Rates for mesotheliomas, on the other hand, are similar for

smokers and nonsmokers exposed to asbestos.

Hammond, Selikoff, and Seidman (156) have

analyzed mortality data from a large group of

U.S. male asbestos insulation workers. Computations were carried out comparing the insulation workers to a control group of males

from a large cohort assembled by the American

Cancer Society (ACS). Table 10 presents the results of the analysis, supporting the existence of

strong synergism between smoking and exposure to asbestos in the production of lung cancer. As the authors explain, if the two exposures

were acting independently in this cohort, one

would predict the following (156):

. . . the lung cancer death rate of asbestos

workers with a history of cigarette smoking

should be very close to the sum of the following

three numbers: 11.3 (the rate for the “no,no”

group), 47.1 (the mortality difference for the

“yes, no” group), and 111.3 (the mortality difference for the “no, yes” group). The sum comes

to 169.7 lung cancer deaths per 100,000 manyears . . . . In contrast, the observed lung cancer death rate of the “yes, yes” group was 601.6

per 100,000 man-years. The difference (601.6 –

169.)7 = 431.9 lung cancer deaths per 100,000

man-years, was presumably due to a synergistic

effect in men with both of the two types of exposure . . , .

Another measure, in addition to the mortality

difference, is the mortality ratio, which in this

case is the lung cancer death rate in each of the

four exposure groups, divided by the lung

cancer death rate in the group of nonsmokers

who were not exposed to asbestos (group 1).

The mortality ratio for exposure to both agents,

53.24, is much higher than would be expected

from the additive effects of cigarette smoking

alone (mortality ratio = 10.85) and asbestos exposure alone (mortality ratio = 5.17). The effects appear to be multiplicative.

Attribution of Risk

In the case of smoking and asbestos, and in

other cases where two or a variety of factors interact to produce some cases of cancers, the

disease may be prevented by interventions in

any of the factors. Shared responsibility, however, complicates the attribution of risk to a

Table 10.—Age-Standardized Lung Cancer Death Ratesa for Cigarette Smoking and/or Occupational Exposure

to Asbestos Dust Compared With No Smoking and NO Occupational Exposure to Asbestos Dust

Exposure to History of Mortality Mortality

Group asbestos? cigarette smoking Death rate difference ratio

Control No No 11.3 0.0 1.00

Asbestos workers Yes No 58.4 + 47.1 5.17

Control No Yes 122.6 + 111.3 10.85

Asbestos workers Yes Yes 601.6 + 590.3 53.24

aRat,s ~~r 100000 man. YearS standardized for age on tfle distribution Of tfle man-years of all the asbestos workers. Number Of lUn9 cancer deaths b=ed on death Certlflcate information.

SOURCE: Hammond, Sellkoff, and Seldman (156)
68 ● Technologies for Determining Cancer Risks From the Environment

particular factor. Adding up the numbers of

cases that might be prevented by various individual measures taken separately may produce

a total number of “preventable” cancers larger

than the number that actually occurs. An example of this concept, presented in table 11, is

based on Lloyd’s (214) analysis of the asbestos

insulation worker mortality data described

above. He estimated the percentage reduction in

lung cancer mortality that would accrue by

eliminating smoking cigarettes alone to be 88.5

percent, and by eliminating exposure to

asbestos alone to be 79.6 percent. By eliminating both exposures, the total reduction would be

97.8 percent, and not the sum of the individual

reductions, which would amount to a whopping

168.1 percent. The multifactorial nature of

Table 1 1.—Estimates of Percentage Reduction in

Lung Cancer Mortality in Asbestos Workers by

Elimination of Exposure to Cigarettes

and to Asbestos

Percentage reduction from

Status current rate

Current. . . . . . . . . . . . . . . . . . . . 0.0

Eliminate smoking only . . . . . . 88.5

Eliminate asbestos only. . . . . . 79.6

Eliminate smoking and

asbestos. . . . . . . . . . . . . . . . . . 97.8

SOURCE: Lloyd (214).

cancer means that it is impossible a present a

neat balance sheet adding up to 100 percent that

indicates the proportion of all cancers that can

be attributed to factors X, Y, and Z.

ESTIMATES OF THE AMOUNTS OF CANCER ASSOCIATED WITH

ENVIRONMENTAL FACTORS

Diverse methods have been used to produce

estimates of the amounts of cancer associated

with various exposures and behaviors. The

methods are variously described as ranging

from “seat of the pants, ” to “top of the head,” to

figures based on more quantified inputs. Evidence for associations between various “factors”

and cancer ranges from very strong to very

weak. There is no relationship between the

strength of the association and the estimated

magnitude of the amount of cancer associated

with a factor. For instance, the strongest associations include those ‘between smoking tobacco

and respiratory cancers, between asbestos and

cancer of the lung and other sites, and between

ionizing radiation and cancer at many sites.

While each of the three associations is strong,

the percentage of cancer associated with each is

different. Smoking is associated with more than

20 percent of cancer, asbestos with between 3

and 18 percent, and natural background radiation, with less than 1 to 3 percent.

The importance of a factor, as measured by

the magnitude of the proportion of cancer with

which it is associated, is one starting point for

deciding on the development of preventive strategies. However, a large proportion, by itself

does not give any indication of the practicality

or availability of strategies. If all factors were

equally well understood, and preventive strategies equally available, one would choose to go

for big reductions. Under real conditions, strategies that can be implemented receive preference.

Most numerical estimates of associations are

based on cancers occurring today or in the last

few years. Therefore, they are not predictors of

carcinogenic activity today, but reflections of

carcinogenic activity in the past, possibly 20 to

50 years ago. A few authors have attempted to

relate today’s carcinogenic risk to future cancers

and these are also cited.

All factors discussed here have not been” investigated equally in the scientific community,

either because of perceived differences in relative importance, or because of difficulty in obtaining meaningful results. Therefore, it has not

been possible for “equal” evidence to be presented for each factor in this assessment. Evidence for carcinogenicity in humans from good

epidemiologic studies is given more weight than

are animal data.
Ch. 3—Factors Associated With Cancer ● 69

The remainder of this chapter discusses what

is known about the contributions of the following factors to cancer incidence and mortality:

tobacco, alcohol, diet, occupation, pollution,

consumer products, medical drugs and radiation, sexual development, reproductive patterns

and sexual practices, natural radiation, infection, and other or unknown associations. Current thinking, with some historical background,

is presented for the major elements of each factor, and attempts are made to mention studies

giving quantified estimates of the importance of

various factors. 1

I Discussion of the factors draws heavily on a contract report by

Sir Richard Doll and Richard Pete, who were charged with reviewing existing literature about the quantified estimates of cancer causation. They also made their own estimates, which are cited in this

assessment. Doll and Pete’s report, in its entirety, is published in

the ]ournul of National Cancer lm-titute (93).

TOBACCO

Diseases related to the smoking of tobacco include lung cancer and cancer at other sites, coronary heart disease and stroke, chronic bronchitis and emphysema, and many other diseases,

including peptic ulcers (157). Tobacco smoking

“is the single most important preventable environmental factor contributing to illness,

disability, and death in the United States” (286).

WHO (365) states:

Smoking-related diseases are such important

causes of disability and premature death in developing countries that the control of cigarette

smoking could do more to improve health and

prolong life in these countries than any single action in the whole field of preventive medicine.

The harmful effects of tobacco are greater

when it is smoked as cigarettes than when consumed in other forms. This may be because acid

cigarette smoke is less irritating than the

alkaline smoke from pipes and cigars and, therefore, more easily inhaled. However, tobacco

consumption in any form appears to be accompanied by adverse effects, most recently demonstrated in a study showing that long-time snuff

dippers experience a highly increased risk of

oral cancer (363).

The categories used are not necessarily “natural” assemblages, nor are they the only possible

groupings of the components. The discussion of

each factor includes a description of important

inclusions and exclusions. For instance, the

“diet” section looks at all “foodstuffs,” including

naturally occurring and added contaminants.

Drinking water, which is discussed under “pollution, ” and “alcohol,” which is treated as a factor unto itself, are excluded from diet.

All of the estimates considered in preparing

the following discussion of factors are listed in

table 19, at the end of this chapter. Only “best

estimates, ” either point estimates or intervals, as

presented by each author are included in the table. The primary references should be consulted

for acceptable ranges and/or confidence limits,

exact data sources and methods, and caveats.

Tobacco is known to contribute more heavily

to the number of cancer deaths than any other

single substance.. The relationship of cigarette

smoking and cancer was first suggested in the

1920’s. During the 1950’s, results from many epidemiologic studies confirmed this association

(287). Many carcinogens have been identified in

cigarette smoke, and the differences consistently

observed between rates of lung cancer among

regular cigarette smokers and lifetime nonsmokers is so extreme that it is not likely to be

an artifact of the epidemiologic method (287):

The 1964 Surgeon General’s Report reached

the following conclusion: ‘Cigarette smoking is

causally related to lung cancer in men . . . The

data for women, though less extensive, point in

the same direction. ’

Today, cigarette smoking is regarded as the major cause of lung cancer in both males and females and is largely responsible for the recent

rapid rise in female lung cancer rates. The 1980

Surgeon General’s report, The Health Consequences of Smoking For Women, states (287):

. . . the first signs of an epidemic of smoking-related

disease among women are now appearing.
70 ● Technologies for Determining Cancer Risks From the Environment

It has been predicted that by the early 1980’s,

the age-adjusted female lung cancer death rate

will surpass the breast cancer rate, which is

today’s leading cause of cancer death in women.

The Surgeon General’s 1980 report estimates

(287):

. . . smoking will contribute to 43 percent of the

male and 18 percent of the female newly diagnosed cancer cases in the United States in 1980

and to 51 percent of the male and 26 percent of

the female cancer deaths.

The principal impact of tobacco smoking is

on the incidence of cancer of the lung although

cancer at many other body sites, including

larynx, oral cavity, esophagus, urinary bladder,

kidney, and pancreas are also associated (287).

By late middle age, the risk of developing lung

cancer is more than 10 to 15 times greater in

cigarette smokers than in lifelong nonsmokers

(152). Present evidence indicates that the effect

of smoking on the development of lung cancer is

affected by number of years smoked, age when

smoking began, the number of cigarettes smoked per day, the degree of inhalation, and the

composition of the cigarette.

Studies have shown that discontinuing smoking decreases the risk of developing lung cancer.

Ten to fifteen years following cessation of

smoking, an ex-smoker’s risk of dying of lung

cancer decreases to a level only about two times

higher than the risk for lifelong nonsmokers

(286). This phenomenon is nicely illustrated by

data in table 12 from an epidemiologic study of

British doctors (92).

Higginson and Muir (166) attributed 30 percent of male and 7 percent of female cancers

from 1968 through 1972 in the Birmingham and

West Midland region of England to tobacco.

They specifically ascribed 80 to 85 percent of

lung cancers to smoking. Wynder and Gori

(368) estimated that 28 percent of male and 8

percent of female 1976 cancer deaths in the

United States can be attributed to smoking.

Their estimate is based on calculating the percent difference between U.S. mortality rates and

the lowest reported worldwide mortality rates

for each site and by considering specific casecontrol studies.

Table 12.—Lung Cancer Mortality Ratios

in Ex.Cigarette Smokers, by Number of

Years Stopped Smoking

Mortality

Years stopped smoking ratio

Still smoking. . . . . . . . . . . . . . . . . . . . . . . . . . . 15.8

1-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . “16.@

5-9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9

10-14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3

15+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.0

Nonsmokers . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.0

aThe higher mortality ratios observed in the 1-4 year Category after quittin9

compared to those continuing smoking is believed to be due 10 those

individuals who quit smoking because of illness,

SOURCE: Doll and Peto (93).

Enstrom (100) reported:

If all Americans did not smoke, the mortality

reduction that would occur has been estimated

to be 80,000 lung cancer deaths plus 22,000

other cancer deaths of the “1978 total of 390,000

cancer deaths—a reduction of 26 percent.

Data from a representative sample of nonsmokers derived from a 1966–68 National Mortality Survey indicated that this group had a

total cancer rate which was 24 percent less than

that of all U.S. whites (100).

Numerous estimates have been made of the

contribution of tobacco to the overall cancer

rate. Most have taken advantage of concurrent

epidemiologic cohort studies, in which large

numbers of people are queried about their

smoking habits at the initiation of the study and

then followed to determine their causes of

deaths. The largest such study involved 1 million Americans who were self-identified as

smokers or nonsmokers in 1959 and whose subsequent mortality was monitored by ACS. The

magnitude of the excess risk observed for

women in the ACS population was less than for

men. The difference is thought to be due to

women having smoked fewer cigarettes per day,

inhaling less deeply, and being more likely to

smoke cigarettes with reduced tar and nicotine

(153). In addition, women are less frequently exposed to occupational hazards, including those

that may act additively or synergistically with

tobacco to cause cancer.

Several researchers have evaluated data from

the ACS study population. Doll and Peto (93)
Ch. 3—Factors Associated With Cancer ● 71

computed mortality rates from the ACS study

group and estimated that between 25 and 40

percent of 1978 American cancer deaths, with a

best estimate of 30 percent (94,782 or 43 percent

male; 27,266 or 15 percent female), could be attributed to tobacco smoking. Their computation

method assumes that the male and female agespecific cancer death rates observed among the

ACS nonsmokers, between 1960 and 1972,

would have applied to the entire country had no

one smoked.

Hammond and Seidman (155) estimated that

from 25 to 35 percent of cancer mortality in the

U.S. male population and 5 to 10 percent in the

female population are “mainly due to smoking

of tobacco products and cigarettes. ” Enstrom

(100) calculated a 38-percent reduction in the

total cancer rate in the “never smoked regularly” group as compared with all U.S. whites.

These estimates from ACS data do not greatly

differ and the reported differences can be explained by the different methodological approaches and assumptions used. Hammond and

Seidman (155) assumed that the age-specific

distribution of smoking habits in the ACS group

was similar to the country as a whole and relied

on mortality rates computed for individuals

classified as smokers in 1959, many of whom

are known to have quit the habit by 1967. In the

approach taken by Doll and Peto (93), it was

unnecessary to speculate on the smoking habits

of the general population and instead of using

mortality rates for smokers, they relied on cancer rates in the nonsmoking group. The specifics

of Enstrom’s (100) calculations were not given.

Data derived from a unique study cohort such

as the ACS population are not free of bias, but

the risks estimated from the study are comparable with those found in a study of U.S.

veterans. Rogot and Murray (312) reported

mortality ratios for cigarette smokers versus

nonsmokers and ex-cigarette smokers versus

nonsmokers in a cohort of 250,000 American

World War I veterans. After a 16-year followup

period, lung cancer deaths occurred 11.3 times

more frequently among smokers; laryngeal cancer 11.5 times, buccal cavity cancer, 4.2 times;

pancreas and bladder cancer, approximately 2

times; and deaths from cancer at all other sites

1.38 times more often (see table 13). Studies

from Great Britain (94,192) and other countries

(286,287) show similar elevated cancer death

rates among smokers.

Many of these estimates have been criticized

for overstating the impact of tobacco on cancer.

Objections are expressed because the studies

measured mortality rather than incidence, and

because they did not take into account improvements in survival, changes in smoking

habits, and changes in cigarette composition.

None of the estimates attempt to account for

any effects of “passive smoking” and it is only

recently that evidence of a carcinogenic effect

Table 13.–Mortality in a Population of U.S. Veterans Classified as Smokers Compared to Mortality Expected

for Nonsmokers

Cigarette smokers Ex-cigarette smokersa

Cause of death (7th Revision lnter- Observed Expected Observed Expected

national Classification of Disease) deaths deaths 0- E

b

deaths deaths 0- Eb

All cancers (140-207). . . . . . . . . . . . . . . . . . . . . . . . 7,608 3,590’ 2.12 2,816 2,025 C

1.39

Cancer of buccal cavity (140-144) . . . . . . . . . . . . . 110 26 4.22 24 14 1.67

Cancer of pancreas (157) . . . . . . . . . . . . . . . . . . . . 459 256 1.79 170 145 1.17

Cancer of larynx (161) . . . . . . . . . . . . . . . . . . . . . . . 94 8 11.49 22 5 4.78

Cancer of lung and bronchus

(162.1, 162.8, 163) . . . . . . . . . . . . . . . . . . . . . . . . . 2,609 231 11.28 517 130 3.97

Cancer of bladder and other urinary

organs (181) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 151 2.16 126 90 1.41

All other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . 4,010 2,916 1.38 1,957 1,642 1.19

aonly ex.cigarette Smokers who stopped smoking cigarettes for reasons other than physicians’ orders.

% + E values are based on expected numbers to two decimal places.

cvalues d. not exactly total due to rounding.

SOURCE Rogot and Murray (312)
.

72 . Technologies for Determining Cancer Risks From the Environment

from such exposure has been documented.

Hirayama (167) reported an approximately twofold increased risk of developing lung cancer

among nonsmoking wives of cigarette smokers.

The effects may even be greater; a fourfold excess was estimated by Doll and Peto (93), who

considered lifelong exposure, as would be the

case with children.

A more precise estimate of the proportion of

cancer associated with tobacco smoking requires a more exhaustive study of lung cancer.

Such an effort might be desirable because of the

importance of lung cancer to overall cancer

rates. As American lung cancer death rates continue to rise, the estimate of the percentage of

cancer deaths caused by tobacco will likewise

increase. The future course of lung cancer rates

depends largely on patterns of cigarette consumption and possibly on changes in tar and

nicotine yields. The latter point may be particularly important in light of the large numbers

of smokers who have switched to lower tar and

nicotine cigarettes.

There is some evidence to indicate that lowtar/nicotine cigarettes may have a lesser carcinogenic risk (6,153,157,287). The tar and nicotine yield is believed to be a function both of

the tar/nicotine content of the tobacco and the

number of puffs taken (202). Therefore, a reduced risk is dependent on the smoker’s behavior as

well as the cigarette itself. The decreased risk

from a “less hazardous” cigarette may be

somewhat offset by an increase in the number of

cigarettes smoked. Reports indicate that with

the increased production of low-tar/nicotine

cigarettes, there has been an increase in the

number of cigarettes consumed per current

smoker (286). It is also unknown whether

chemicals newly added to cigarettes and

changes in the composition of the gaseous phase

will have health consequences.

The extent to which the increase in male and

female lung cancer rates over the last few decades can be accounted for by tobacco is debated. Doll and Peto (93) argue that the increase

within the last century can almost totally be explained by cigarette smoking, while others,

Schneiderman (321) and the Toxic Substances

Strategy Committee (345) included, contend

that additional factors are responsible. (For a

more complete discussion, see ch. 2.)

Examination of cigarette-consumption patterns in this country leads to speculations about

future cancer statistics at tobacco-related sites.

The proportion of adult men smoking cigarettes

has declined from 51 to 37 percent during the

period 1965 to 1978 (287). There has also been a

slowdown in the rate of initiation of smoking

among adolescent males. The decreases began at

the time of release of the first Surgeon General’s

report in 1964, and the widespread discussion of

the dangers of smoking that followed (287).

This information demonstrates that worthwhile

decreases in cigarette consumption can take

place even without radical Government intervention, chiefly by increasing public awareness

of the hazards of smoking. The proportion of

adult women who smoke remained virtually

constant at around 32 percent between 1965 and

1976, and has since started declining slightly.

Unfortunately, the rate of smoking initiation

among young women has not declined (287).

Changes in smoking habits that should lower

risks are believed to have already influenced

lung cancer rates. The rate of increase in lung

cancer among men under 65 years of age has

slowed during the last decade (see table 8 and

fig. 10). Recent female mortality statistics are

also promising, for they indicate that female

lung cancer rates in the 30- to 4&year age group

are steady or decreasing. There is reason to

hope that with continued reductions in exposure

to the harmful components of cigarettes, the decreases will follow through to older age groups.

Public health laws exclude tobacco from regulatory action because smoking tobacco is

viewed as a personal decision, and one in which

Congress has decided not to intervene. The

Government limits its responsibility to informing smokers and potential smokers of the

hazards of cigarettes, conducting behavioral

studies on ways of affecting smoking habits,

and supporting research on low-tar/nicotine

cigarettes.
Ch. 3—Factors Associated With Cancer ● 73

ALCOHOL

Alcohol is considered next because of the interaction between tobacco smoking and alcoholrelated cancers. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) (257) estimated that approximately one-third of adult

Americans drink alcoholic beverages at least

once a week and another third do not drink so

regularly but drink primarily on special occasions. In addition, NIAAA estimated that there

are 9.3 to 10 million “problem drinkers, ” including alcoholics, in the adult population.

Alcohol consumption is influenced by numerous

personal characteristics including sex, age,

education, socioeconomic status, occupation,

residence, ethnicity, and religious affiliation.

Alcohol’s association with cancer was first

suspected around the turn of the century. Today, as is the case with tobacco, there is indisputable evidence that alcohol consumption

increases the risk of developing cancer at

various body sites. The 1978 Department of

Health, Education, and Welfare (DHEW) report, Alcohol and Health (257), states:

In comparison to the general population,

heavy consumers of alcohol always show a

marked excess of mortality from cancers of the

mouth and pharynx, larynx, esophagus, liver,

and lung. In the United States, these cancers

range from 6.1 to 27.9 percent of the total incidence of all cancer recorded in those locations

where there are cancer registries.

Epidemiologic studies have demonstrated that

cancers are more common in men employed in

trades that encourage the consumption of large

amounts of alcohol. A recent study showed that

Danish brewery workers have a higher risk of

developing cancer then the general population

(193). Clinical evidence suggests that consumption of alcohol at levels sufficient to cause

cirrhosis of the liver also increases the incidence

of liver cancer (257).

Researchers have tried to determine whether

the association between alcoholic drink and

cancer is due to the alcohol itself or to other

chemicals found in spirits, wines, and beers

(348). Pure grain alcohol (ethanol) has not been

shown to be carcinogenic in animal bioassays

(93,277); however, both pure ethanol and methanol, a contaminant of many alcoholic beverages, are mutagenic in bacteria (160,277). Additionally, many alcoholic drinks are found to be

mutagenic. The resuIts from such experiments

do not yet lead to firm conclusions, but it may

be that components of alcoholic beverages as

well as alcohol itself are related to increased

cancer risk. Some evidence suggests that the risk

of cancer is greatest when alcohol is consumed

as spirits and that the apple-based drinks consumed in Northwest France are particularly

harmful (93). However, the carcinogenic effect

of alcoholic beverages is largely independent of

the form in which it is drunk. In addition to a

direct effect, alcohol may also exert a carcinogenic effect by facilitating contact between extrinsic carcinogenic chemicals and the contents

of the stem cells that line the upper digestive

tract and larynx.

Epidemiologic evidence supports the view

that excessive alcohol consumption increases

the risk of developing cancers of the mouth (excluding lip), larynx, and esophagus and that

alcohol acts additively and even synergistically

with tobacco in the pathogenesis of cancers of

the upper digestive tract (257,367).

Most estimates of the percentage of cancer

associated with alcohol fall in the 3- to 5-percent

range. From data presented by Schottenfeld

(233), alcohol appears to be associated with 4 to

5 percent of 1978 U.S. cancer deaths; Wynder

and Gori (368) estimated 4 percent male and 1

percent female 1976 U.S. cancer incidence; and

Higginson and Muir (166) estimated 5 percent

male and 3 percent female 1968–1972 cancers in

the Birmingham and West Midland region of

England.

Rothman (313) (see table 14) and Doll and

Peto (93) estimated that 3 percent of U.S. cancer

mortality is related to alcohol. Rothman’s

calculations are based on attributing a proportion of 1974 cancer deaths at each alcoholrelated body site to alcohol consumption. Doll

!30-4’31 o - 81 - 6
74 ● Technologies for Determining Cancer Risks From the Environment

Table 14.—Praportion of Cancer Deaths Attributable to Alcohol Consumption by Site and Sex

Males Females

Number of Number of

deathsa

Percent ascribedb Number of deaths deathsa

Percent ascribedb Number of deaths

Body site from cancer to alcohol ascribed to alcohol from cancer to alcohol ascribed to alcohol

Buccal

cavity and

pharynx . . . 5,686 50 2,843 2,282 40 913

Esophagus . . 4,917 75 3,688 1,735 75 1,301

Liver. . . . . . . . 1,600 30 480 865 30

Larynx . . . . . . — 2,826— 50 1,413 436 40 174

Total. . . . . . 15,029 8,424 5,318 2,648

Total cancer

deaths . . . . 199,194 4.2 166,338 1.6

aln 1974.

bpropo~lon of alcohol. cause~ cancer at each site from (313).

SOURCE: Adapted from Rothman (313).

and Peto assume that cancers at sites related to

alcohol consumption account for 7 percent of all

cancer deaths in men and 3 percent in women.

They attribute to alcohol about two-thirds of

these cancer deaths in men, about one-third in

women, plus a small proportion of the liver

cancer deaths (which constitute less than 1 percent of all cancer deaths) and derive overall

estimates for the combined sexes of 3 percent

(range: 2 to 4 percent:). It should be emphasized

that most of the cancer risk posed by alcohol

consumption is also related to cigarette smoking. Therefore, most of the cancer deaths caused

by alcohol would be avoided in the absence of

smoking even if alcohol consumption remained

unchanged.

Table 15 shows annual incidence rates for alcohol-related cancer sites for several regions in

the United States where cancer registries exist

(348). Among the white population, the proportion of total cancer incidence associated with

Table 15.—Age-Adjusted Annual incidence Rates for Selected Cancer Sites in Various Population Groups in

the United States

Total for Proportion

the 7 01 all

Place Population Tongue Mouth Oropharynx Hypopharynx Esophagus Liver Larynx cancer sites cancers (O/.)

California:

Alameda White 3.0

Black 2.2

3.6

13.2

3.7

4.1

2.2

2.2

1.1

1.5

2.2

4.3

7.9

12.9

23.7

40.4

8.5

12.3

13.6

12.5

Bay Area White 3.2

Black 2.1

4.2

4.8

2.6

3.3

2.1

1.5

1.5

4.0

15.2

2.8

4.2

7.5

11.8

25.8

42.9

Connecticut 2.8 4.3 1.5 5.7 2.0 7.8 26.2 9.2

Iowa 1.4 2.6 1.1 1.2 3.0 1.6 5.8 16.7 6.7

Detroit White 2.7

Black 3.3

3.3

3.3

2.0

2.1

1.2

1.1

4.0

14.1

2.6

4.5

7.5

7.7

23.3

36.1

&7

11.3

New Mexico Spanish 0.4

Other white 2.2

0.7

2.8

0.4

1.4

0.2

3.0

2.2

3.0

3.0

3.1

2.7

5.8

9.6

18.6

6.1

6.7

New York State 2.2 3.2 1.3 0.8 4.5 1.9 5.9 19.8 8.0

Puerto Rico 7.5 7.8 4.3 4.4 14.8 3.3

0.9

6.4 48.5 27.9

Utah 2.1 2.5 0.9 0.4 1.8 4.4 13.0 6.1

SOURCE: Tuyns (348)
Ch. 3—Factors Associated With Cancer ● 75

alcohol varies from 6.1 to 9.1 percent but

reaches 11.3 to 12.5 percent among blacks. The

highest proportion, 27.9 percent, is found

among people living in Puerto Rico. It should be

noted that these data refer only to those cancers

for which an obvious association with alcohol

consumption has been demonstrated.

Estimating the proportion of cancer attributable to alcohol alone is hindered by the

difficulty of obtaining accurate data on the

amount of alcohol consumed. Results of studies

must also be interpreted with caution in view of

the fact that individuals who do not drink are

often distinguished by behavioral characteristics

very different from those seen in drinkers, many

of which may affect cancer incidence.

Figure 18 depicts the relative risk of developing esophageal cancer in relation to different

Figure 18.—Relative Risks of Esophageal Cancer

in Relation to the Daily Consumption of

Alcohol and Tobacco

Number of

alcoholic drinks ‘~ \

\

\

\

\

\ O-3 \\ 3-6

‘~

20+A ● 

\ ‘s.1 \ 123 \ 44.4

\ \

Number of

cigarettes

---

10-19

3.4 8.4 19.9 *.L ---- 1

10-k 9/ Ii\

I uoa~~v

\

%

- - -

\u\

0-9

m

\ 1.0 7.3 tao

o-9 g \ ‘

\

.

0-40 g 41-80 g 81+ g

Alcohol

Note: The risk is 44.4 times greater for individuals consuming 20 g or more of

tobacco and 80 g or more of alcohol per day (upper right block) than for individuals consuming little or none of either drug (lower left block). One ounce of

ethyl alcohol is approximately 23.4 grams, thus 40 grams is 1.7 oz. or approximately equivalent to 3 drinks.

SOURCE National Institute on Alcohol Abuse and Alcoholism (257)

smoking and drinking habits. The risk of the

nonsmoker developing cancer from the

consumption of even very large amounts of

alcohol is small.

Feldman et al. (118) found that the risk of

head and neck cancer was 6 to 15 times greater

in heavy drinkers who smoked than in nondrinkers and nonsmokers. Nonsmoking drinkers had a “slightly” higher risk (around 1.5) than

total abstainers while nondrinking or light

drinking smokers had 2 to 4 times the risk.

Breslow and Enstrom (32) correlated average

annual age-adjusted cancer mortality rates for

the period 1950-1967 with per capita consumption of cigarettes, spirits, wine, and beer as

estimated from 1976 tax receipts in 41 States. As

expected, respiratory cancers were related to

cigarette consumption. They also found a correlation between consumption of spirits and certain cancers of the upper alimentary tract. In addition, cancers of the stomach, large intestine,

kidney, bladder (for men), and breast (for

women), were correlated with spirits consumption. The strongest correlation was found between rectal cancer and beer consumption. This

finding was also observed in a separate analysis

involving 24 countries.

A retrospective study of male veterans by

Rothman and Keller (315) demonstrated individual effects for smoking and drinking and

synergistic effects for cancers of the mouth and

pharynx. Both they and Schottenfeld (323) calculated that 76 percent of cancers at alcohol and

tobacco-related sites, which represents 36 percent of total male cancer mortality, could

be eliminated if drinking and smoking were

avoided.

Examining trends of alcohol consumption

permits some speculation about future cancer

rates. Quantitative estimates cannot be made,

but several factors highlighted in the Third

Special Report to the U.S. Congress on Alcohol

and Health (257) indicate that alcohol will increase in importance as a carcinogenic factor:

● Increased availability of alcoholic beverages has occurred as a result of the lowering

of the drinking age in several States, a trend

to longer hours of sales, and an increase in
76 ● Technologies for Determining Cancer Risks From the Environment

●

●

●

the number of retail outlets. (Recently, several States have raised drinking ages. )

Around 1960, total per capita sales of absolute ethanol began to rise significantly

registering a 30-percent gain between 1961

and 1971. Since 1971, there has been virtually no change in per capita sales. The effect of the overall increase may not yet

have fully manifested itself in cancer rates.

There is particular concern over increased

alcohol consumption in youths. This is

heightened by the observation that early

drinking behavior predicts drinking habits

in later life.

The proportion of high school students

who reported ever having been drunk increased dramatically from 19 percent

before 1966 to 4.5 percent between 1966 and

1975. The proportion reporting being intoxicated at least once a month rose from

DIET

Introduction

Studying the relationship of diet and health is

a continued source of frustration and excitement. Food affects all body functions and comes

into direct contact with the digestive system and

indirect contact with all other organs. Cancer

rates for digestive sites vary considerably

around the world and have prompted studies of

diet’s role in cancer causation.

As discussed here, diet encompasses those

items ingested as food, including substances

added to food, those produced during normal

cooking, storage, and digestion, but excluding

drinking water and alcohol (discussed in this

chapter under Air and Water Pollution a nd

Alcohol, respectively).

The amounts and balance of the major components of diet are generally believed to be

responsible for the lion’s share of diet-related

cancers. Deficiencies or excesses of microelements, and the presence of additives or contaminants, are probably less important. The

various means by which diet may influence the

10 percent before 1966 to 19 percent between 1966 and 1975.

The importance of alcohol as a health hazard

is not limited to its association with a relatively

small percentage of cancer. Estimates of the annual number of deaths related to alcohol range

from 37,000 to 205,000. Cirrhosis of the liver,

the seventh leading cause of death in the United

States, was responsible for 30,066 deaths in

1978. As an contributory cause of homicides,

suicides, and accidents, alcohol’s toll is even

greater. The Institute of Medicine (178) recently

completed a study of alcoholism and related

problems and indicated several opportunities

for research. These included further research on

alcohol metabolism, development of appropriate animal models, and further efforts

through epidemiologic studies to explore the

link between alcohol and its adverse health consequences.

development of cancer are listed in table 16.

Diet also plays a role in the treatment of cancer

illustrating the pervasive role of diet with

respect to all aspects of the disease.

Unfortunately, dietary studies are plagued

with methodological problems and conflicting

evidence exists for almost every specific question that has been investigated. The overall

association of cancer with diet exists but there is

no reliable indication of exactly what dietary

changes would be of major importance in reducing cancer incidence and mortality.

The strongest positive associations identified

through correlations of dietary patterns and

cancer rates are those between total fat intake,

particularly animal fat consumption and cancers of the breast and endometrium; and between total protein intake and cancer of the colon. The most dramatic change observed in a

diet-related cancer site has been the reduction in

incidence and mortality from stomach cancer.

In the United States, the 1950 age-adjusted

mortality rate from stomach cancer was 24.4/

100,000 for males and 13.1/100,000 for females
Ch. 3—Factors Associated With Cancer ● 77

Table 16.—Some Currently Attractive Hypothetical or Actual Ways

in Which Diet May Affect the Incidence of Cancer

Possible ways or means Example a

Ingest ion of powerful, direct-acting carcinogens or t heir Carcinogens in natural foodstuffs (plant products)

precursors Carcinogens produced in cooking

Carcinogens produced in stored food by microorganisms

(bacterial and fungal)

Affecting the formation of carcinogens in t he body Providing substrates for the formation of carcinogens in the

body (e.g., nit rites, nitrates, secondary amines)

Altering intake or excretion of cholesterol and bile acids (and

hence the production of carcinogenic metabolizes in the

bowel)

Altering the bacterial flora of the bowel (and hence the capacity to form carcinogenic metabolizes)

Affecting transport, activation, or deactivation

of carcinogens

Altering concentration in, or duration of contract with, feces

Altering transport of carcinogens to stem cells

Induction or inhibition of enzymes (which affect carcinogen

metabolism or catabolism)

Deactivation, or prevention of formation, of short-lived intracellular species (e.g., by use of selenium, vitamin E, or

otherwise trapping free radicals; by use of b-carotene or

otherwise quenching singlet oxygen; by use of other antioxidant)

Affecting “promotion” of cells (that are already

initiated) b

Vitamin A deficiency (clinical or subclinical)

Retinol [Binding Protein] (hormonal and other factors determine blood RBP, though vitamin A intake may not affect it

much)

Otherwise affecting stemcell differentiation (carotenoids?

determinants of lipid “profile”?)

Overnutrition Age at menarche

Adipose-t issue-derived estrogens

Other effects

aThere may be considerable overlap between many of the efltrleS In this table

bor, more ~enerally, affecting the ~robablllty that a partially transformed stem cell will become fully transformed and Will proliferate successfully Into Cancer

SOURCE Doll and Peto (93)

while in 1977 the rate was 8.8/100,000 for males

and 4.0/100,000 for females. This decrease has

occurred in many other countries, including

those with high initial rates, such as Japan and

Iceland, and those with lower initial rates, such

as Canada and New Zealand. The factors believed to have contributed to these decreases include: reduction in use of salt and pickling,

lower consumption of smoked foods, and increased use of refrigeration, increased consumption of milk, green vegetables, fruit, and

antioxidants (237).

In general, as a result of increased intake of

calories, proteins, and certain other nutrients,

Americans have been growing taller and reaching sexual maturation earlier. A great improvement in the Nation’s health has resulted from

this change, but increased risk for certain cancer

sites may accompany the improvement. For example, earlier sexual maturation in women is

associated with higher risk of breast cancer later

in life, though as yet, no increases in breast

cancer has been attributed directly to improved

nutrition (see Sexual Development, Reproductive Patterns, and Sexual Practices for a more

complete discussion of this topic).

Many estimates of the importance of diet to

cancer have been put forth. Doll and Peto (93)

estimated that altering dietary practices may

reduce cancer by as much as 35 percent (stomach and large bowel cancer by 90 percent; endometrium, gallbladder, pancreas, and breast

by 50 percent; lung, larynx, bladder, cervix,

mouth, pharynx, and esophagus by 20 percent;

others by 10 percent). The great uncertainty of

this estimate is indicated by the range of 10 to 70

percent which they attach to their estimate.

Wynder and Gori (368) estimate, by calculating
78 ● Technologies for Determining Cancer Risks From the Environment

the percent difference between U.S. mortality

rates and the lowest rates reported worldwide

and by considering specific case-control studies,

that an even larger proportion of cancer, approximately 40 percent in males and 60 percent

in females, could be attributable to diet.

In testimony before the Subcommittee on

Nutrition of the Senate Committee on Agriculture, Nutrition, and Forestry, Dr. Arthur

Upton (353), then-Director of the National Cancer Institute (NCI), succinctly discussed the extent of involvement of diet and cancer when he

stated:

Despite the impression that cancers are linked with

dietary patterns and the inability to pinpoint specific

dietary carcinogens, scientists generally agree that

factors in diet and nutrition-including drinking

water contaminants—appear to be related to a large

number of human cancers, perhaps approaching 50

percent.

Dietary Intake

Fat/Meat Intake

Examination of cancer rates in different countries show positive correlations between colon

cancer and consumption of meat and animal

protein and between cancer of the breast and endometrium with total fat consumption (17).

These cancers are common in the United States,

Canada, and Western Europe and rarer

throughout the developing world.

The most widely held theory is that fat in the

diet has a promotional effect on the development of cancer. One suggested mechanism is

that fats affect hormone levels. Several cancers,

including breast, ovarian, and endometrial are,

in turn, influenced by hormones. This association of dietary fat with higher cancer rates is,

however, not found uniformly. Breast and colorectal cancers are not uncommon among vegetarians, and the observed incidence in Seventh

Day Adventists who are largely vegetarian, is

matched by the same incidence in Mormons

who eat meat (293). This finding and the fact

that meat intake among Mormons is not markedly lower than among the general population is

often cited as a rebuttal to the meat/fat cancer

causation hypothesis. These interpretations

should be viewed cautiously for the studies may

not have been adequate to reflect any promotional effect in these low risk groups who are

less exposed to many other types of carcinogenic stimuli, such as, cigarettes and alcohol,

than is the general population. Additional

studies in this area are needed.

More and more, studies have focused on

specific types of fat. Evidence suggests that diets

with a high ratio of polyunsaturated fats (mainly of vegetable origin) to saturated fats (mainly

of animal origin) may increase the risk of cancer. Paradoxically, this type of diet is recommended to lower the risk of heart disease. Results from epidemiological studies (98,290) and

animal trials (53,305) have been inconsistent

and confusing, and have shown different effects

on different cancer sites. In rats, polyunsaturated fats need be only a small proportion

of a total high fat intake to promote breast

tumor incidence. If the animal model is applicable to humans, virtually all high-fat diets

will exert a promotional effect (52).

Serum cholesterol has been investigated in

many studies as a risk factor for various

cancers. Serum levels are directly affected by intake of cholesterol and fat. A diet with a low

saturated fat to polyunsaturated fat ratio

decreases the amount of ingested cholesterol

that will appear in the serum. The discovery

that the stools of colorectal cancer patients contain an abnormally high proportion of acid

steroids, derived from bile salts, and cholesterol, supports the hypothesis that certain

types of fat play a role in the production of colorectal cancer.

A recent epidemiologic study found an association between high-density lipoproteins and

cancer risk (199). On the other hand, in a prospective epidemiologic study of heart disease in

Framingham, Mass., serum cholesterol levels

were inversely associated with the incidence of

colon cancer and other sites in men. Men with

the lowest serum cholesterol levels experienced

a colon cancer rate which was three times higher

than men with the higher cholesterol levels

(361). A similar negative association was reported in data from the Paris Prospective Study

of Coronary Heart Disease (45).
Ch. 3—Factors Associated With Cancer ● 79

The hypothesis that dietary cholesterol plays

a direct role in the production of colon cancer is

supported by some animal studies. For instance,

the addition of cholesterol to the diet of rats on a

cholesterol-free liquid diet, had a promotional

effect and cholesterol enhanced the carcinogenic

effect of a known carcinogen (1,2 dimethylhydrazine).

Fiber Intake

Burkitt (40) observed that several intestinal

diseases that are common in developed countries are rare in rural Africa where unprocessed

food is consumed, and the stools tend to be soft,

bulky, and frequent. It is suggested that dietary

fiber may reduce colorectal cancer by decreasing the time stools remain in the bowel, by increasing bulk (thereby decreasing the concentration of carcinogens in stool), or by perhaps

altering the distribution of bacteria, some of

which may produce or destroy carcinogenic metabolizes.

The effects of fiber on cancer incidence have

attracted much interest but remain problematical. As in the case of fats, dietary fiber is a term

which covers a multitude of different substances, each of which may have different influences on carcinogenesis. The methods by which

types of fiber are chemically characterized are

still in a primitive state, and analyses of the

composition of dietary fiber in many foods is

lacking. Despite the drawbacks, some associations have emerged. A close inverse correlation

has been found between the pentose fiber content of the diet and mortality from colon cancer

in part of the United Kingdom (93). No correlation was shown with any other fiber types, or

with dietary fiber as a whole.

Elements and Vitamins

Several metals and vitamins are linked with

cancer development. They can either act as carcinogens themselves or they may biologically

compete with other dietary constituents to

enhance or suppress a cancerous response.

An iron-deficient syndrome was shown to be

associated with a high risk of developing cancers of the pharyngeal and esophageal mucosa

in northern Scandinavia. The incidence of

gastric cancer is found to be 4 to 5 times higher

in countries where iron deficiency is prevalent

than in the United States (356).

Selenium, an effective antioxidant, is often

found at higher levels in plants, milk, or human

blood in sections of the United States with low

cancer rates. Selenium deficiency in rats consistently increases the carcinogenic effect of

known chemical carcinogens, particularly in

animals fed on high polyunsaturated fat diets

(190). Supplementation with selenium above

dietary requirements decreases tumor yield in

animals on both low- and high-polyunsaturated

fat diets (188).

Stocks and Davies (24) found that a high zinccopper ratio in soils was associated with

elevated rates of human stomach cancer while

Strain et al. (24) reported an association of

elevated cancer rates with low zinc-copper

ratios. Marginal zinc deficiency is associated

with increased esophageal cancer in animals

(122) and esophageal cancer patients had lower

levels of zinc in their blood, hair, and tumor

tissue than controls in a study of Chinese men

(211). Zinc deficiency may interact synergistically with alcohol to enhance esophageal carcinogenesis (135).

The overall relationship between cancer and

vitamins is not well understood. Vitamin C has

been shown to reduce carcinogen formation in

experimental animals (359), and this activity

may be important in reducing cancer occurrence. Vitamin A (retinol) has been more exhaustively studied than any other vitamin (for

review see 292) and it has been suggested that

vitamin A, or, more particularly, its vegetable

precursor, beta-carotene, may decrease the susceptibility of a variety of epithelial tissues to the

development of cancer. Retinol (or its analogs

retinoic acid and various retinoids) has been

repeatedly demonstrated to diminish the risk of

experimentally induced cancer in laboratory

animals (93). These results are particularly intriguing because the protective effect is observed

even when these substances are fed long after

the animal is treated with an initiating carcinogen, and the vitamin and its analogs appear

to be effective at a wide variety of sites.
80 ● Technologies for Determining Cancer Risks From the Environment

People with a history of consuming above

average amounts of provitamin A (beta-carotene) have a slightly lower incidence of several

different types of cancer than people who give a

history of consuming less. Beta-carotene is

found in carrots, green leafy vegetables and in

red palm oil which is used for cooking in many

tropical countries. Further epidemiologic studies

are now in progress in areas where red palm oil

is habitually used. The role of beta-carotene in

cancer prevention is still uncertain and this particular hypothesis has been mentioned to illustrate the potential importance of diet.

Local deficiency of folate (a B-complex vitamin) has been demonstrated in the abnormal

cervical tissue of some women taking oral contraceptives. The observed abnormalities are

often precursors of cervical cancer. Supplementation with folic acid in these women can reverse the abnormality and appears to prevent

progression to carcinoma (41). Deficiencies of

lipotropes (choline, methionine, and folic acid)

increased the susceptibility of animals to a

variety of environment carcinogens in several

studies (311).

Dietary Balance

Studies in laboratory animals have shown

that altering gross aspects of diet can have substantial impact on the risk of an animal developing cancer. Jose (195) reviewed several reports which demonstrate that restricting calorie

intake without modifying the proportion of the

individual constituents reduces the incidence of

spontaneous tumors and of a variety of cancers

produced by exposure to known carcinogens.

Not only did calorie restriction result in decreased incidence of tumors, but it also delayed

the time of appearance of tumors, and when

tumors appeared, they grew and metastasized

more slowly. The life spans of animals on

restricted diets were often increased up to 50

percent compared to normally fed controls.

However, decreased calorie intake, when accompanied by inadequate protein intake makes

laboratory animals more susceptible to many

environmental carcinogens (47).

A suspected association between obesity and

the risk of cancer was strengthened in an epidemiologic study conducted by ACS which followed 750,000 people from 1959 to 1972 (207).

Overall cancer mortality was found elevated for

those individuals who were more than 40 percent heavier than average. Mortality from cancers of the colon and rectum were increased

among men while mortality from cancers of the

gallbladder and biliary passages, breast, cervix,

endometrium, and ovary were increased among

women. The meaning to be attached to the results is not entirely clear since weight is associated with a variety of social and behavioral

characteristics that affect the risk of cancer in

other ways, including smoking habits and socioeconomic status. Another concern is that diagnosing cancers may be more difficult in obese

individuals, and cancers may generally be more

advanced when they are detected.

In addition to the quantity and composition

of food, the timing of intake has also been

shown to be important. For example, Roe and

Tucker (cited in 93) randomized mice with a

high spontaneous incidence of mammary tumors, between continuous feeding, in which the

mice were fed 6 g of food each day, which they

consumed in frequent small amounts, and intermittent feeding, in which food was limited to 5 g

per day which was eaten at once. No clear difference in longevity was observed, but nonfatal

spontaneous mammary tumors arose in 64 percent of the continuously fed mice and in only 8

percent of those fed intermittently.

Immune function in both humans and animals can be severely compromised by deficiencies of certain dietary nutrients—in particular,

protein, methionine, choline, folate, vitamin

B12, vitamin A, zinc, and pyridoxine (147). Deficiencies in certain of these nutrients, with a concomitant depression of immune system function

have been demonstrated in animals and are suspected of increasing the susceptibility of developing certain cancers (356).

Naturally Occurring Carcinogens

and Precursors

Along with the major components, thousands

of chemical substances occur in small quantities

in foods. Most naturally occurring carcinogens
Ch. 3—Factors Associated With Cancer ● 81

and mutagens are of plant origin, but an important class, nitrates and nitrites, occurs in both

plants and animals.

Nitrates and Nitrites

Nitrate and nitrite salts naturally occur in

vegetables, fish, and meat, are added to food for

their preservative properties (see Additives p.

82), and are present in pesticide and drug

residues in food (127). They react with other

chemicals in the body to produce N-nitrosamines and N-nitrosamides. N-nitrosamines

are among the most powerful chemical carcinogens in laboratory animals, producing tumors at a variety of sites including liver, kidney,

lungs, esophagus, bladder, pancreas, trachea,

nasal cavities, and peripheral nervous system

(221). Experimentally, vitamin C has been

shown to inhibit the formation of nitrosamines

(359).

Epidemiological evidence linking nitrites and

nitrates to cancer is fragmentary. Evidence for a

relationship between gastric cancer and the nitrite content of the diet is not wholly consistent.

It is notable that vegetables, which are usually

the main source of dietary nitrates, appear to

protect against the development of the disease,

possibly because of their vitamin C content (93).

On present knowledge, the possible contribution of dietary nitrates and secondary amines to

the production of cancer is uncertain.

Other Substances

Cycasin in the cycad nut, safrole in sassafras,

pyrrolizidine alkaloids in some plants, and extracts of coltsfoot and bracken fern are a few

naturally occurring compounds which exhibit

carcinogenic properties in animals. Only

bracken fern has been demonstrated to cause

cancer in man. Bracken fern is commonly eaten

in Japan, and Japanese who eat it daily have

three times the risk of developing cancer of the

esophagus as Japanese who do not eat it at all

(93). It has been postulated that the high bowel

cancer rates in Scotland may be due to the ingestion of cattle fed on bracken fern or the leaching

of the carcinogenic components into water or

food (24). Range-fed cattle and sheep may pass

pyrrolizidine alkaloids along to humans in their

meat and milk (215).

Certain plant-derived preparations are associated with cancer. Extracts of some plants used

to make herbal infusions, for use as home remedies, tonics or beverages, are carcinogenic in

animals, and their tannin-containing fractions

are particularly active. Some population groups

who use these products have high rates of

esophageal cancer, suggesting an association

(297). Perhaps of greater concern, because of its

widespread use, coffee has been associated with

human bladder (24) and pancreatic cancer (220),

but whether the associations are causal is not

yet known. Studies in animal cell cultures have

shown caffeine, a constituent of both coffee and

tea, to potentate the effect of carcinogenic

substances (96).

Mutagenic substances have also been identified in cruciferous plants (cabbage, broccoli,

etc.), from cereal grains, and some grazing

range plants in the Southwestern United States

(MacGregor, 1980). Other not-yet-identified

carcinogens and mutagens may occur naturally

in food, but on present evidence, naturally occurring carcinogens are not regarded as an important cause of cancer in the United States (93).

Carcinogens and Precursors Produced

by Cooking

Another possible source of carcinogens is

their production in cooking. Humans are the only animals that cook their food, and it has been

known for many years that carcinogenic chemicals such as benzo(a)pyrene (B(a)P) and other

polycyclic hydrocarbons are produced when

meat or fish is broiled or smoked or when food

is fried in fat which has been used repeatedly,

Sugimura et al. (336) demonstrated that broiling

also produces powerful mutagens that cannot be

accounted for by the production of B(a)P alone.

Few people eat more broiled foods than Americans and while the declining stomach cancer

rate provides some assurance that cancer at that

site is not related to broiled food, the possibility

remains that colorectal cancer, which has not

decreased materially, might be related, Recent
evidence has shown that mutagens can in fact be

produced by cooking at relatively low temperatures (100-200C) (93).

Contaminants

Natural Contaminants

A less obvious source of carcinogenic activity

and one that was overlooked altogether until the

early 1960’s, is the production of carcinogens by

micro-organisms in stored food. Aflatoxin, a

product of the fungus Aspergillus flavus, is the

most powerful liver carcinogen known for some

animal species. In addition, human liver cells

contain the enzymes necessary to produce the

metabolic products that appear to be responsible for its activity. l-here is evidence for believing that aflatoxin is a major factor in the production of liver cancer in certain tropical countries where it is a contaminant of carbohydrate

foods, particularly grains and nuts. The incidence rates of primary liver cancer in different

parts of Africa are approximately proportional

to the amount of aflatoxin in the diet (212).

Liver cancer occurs more commonly in people

who are chronically infected with hepatitis B

virus and it seems probable that where aflatoxin

is present in the diet, both aflatoxin and hepatitis B virus contribute to the risk of liver cancer,

each multiplying the other’s effects.

In the United States, primary cancer of the

liver is a rare disease accounting for less than 1

percent of cancer deaths (2,796 deaths in 1978).

The amount of aflatoxin in the American diet is

small and is only one among several other possible causes of liver cancer. In the American context, the chief importance of the discovery of the

dangers of aflatoxin is that it raises the possibility that other as yet unrecognized mycotoxins in

food may be carcinogenic. Recently, there has

been some evidence to suggest that a fungus

may contribute to the high incidence of esophageal cancer in parts of China by increasing the

nitrite content of contaminated food (209).

Environmental Contaminants

In late 1979, OTA (284) examined both regulatory approaches and monitoring strategies

for coping with contaminated food. A wide

variety of industrial products ranging from

heavy metals and pesticide residues, to substances that leach out of packaging, such as

polyinyl chloride, can pollute food. Organic

compounds are felt to pose the greatest potential

for environmental food contamination based on

the number, volume, and toxicity of organics

manufactured in the United States.

Polycyclic aromatic hydrocarbons (PAH) are

found widely in all types of foods, sometimes at

the same level which can be present in charcoalbroiled meats and smoked ham, i.e., up to 15 ug

B(a)P/kg net weight. Some shellfish and finfish

from polluted waters have been reported to contain up to 1,000 ug B(a) P/kg. The importance of

ingested B(a)P in cancer induction is uncertain.

Epidemiologically, no relationship has been established, and when cancer is produced experimentally in laboratory animals, it either affects

an organ not represented in man or occurs by a

mechanism that does not appear relevant (93).

Some chlorinated hydrocarbons that were

used as pesticides (e.g., DDT, aldrin, dieldrin)

produce liver tumors (hepatomas) in mice, and

some have been shown to be carcinogenic in

other species. These compounds accumulate in

human fat, but no increase in liver tumors appears to have accompanied their introduction

and use. However, the latent period is not

known, and the possibility exists that effects

may be seen some years from now. Pesticide

residues in the form of secondary amines may

constitute a hazard if the formation of nitrosamines in the stomach proves to be a cause of

cancer in man.

Many other chemicals fall into this category

of environmental contaminants. The extent to

which these have contributed to the production

of human cancers is difficult to evaluate, but

believed to be small (328).

Additives

Chemicals are used to preserve food and give

it color, flavor, and consistency. Food dyes

were among the first chemicals investigated because of their structural similarities to accepted

chemical carcinogens (24). Consumption of
Ch. 3–Factors Associated With Cancer ● 83

chemicals by consumers who are unaware of

their presence is partially responsible for the

food safety laws. The laws require that newly

introduced direct food additives be carefully

screened in the laboratory before they may be

used.

Some definitely carcinogenic chemicals,

which have now been withdrawn from foods,

were used for a time before their carcinogenicity

in animals was discovered. These include butter

yellow, thiourea, and a food preservative used

in Japan. The number of cancers, if any, which

these additives produced is unknown. Doll and

Peto (93) estimated an attribution of less than 1

percent of total cancer mortality to food additives.

Of the many food additives presently used in

the United States, three require special consideration: the artificial sweeteners cyclamates and

saccharin, butylated hydroxytoluene (BHT),

and nitrites and nitrates.

Cyclamates were shown to produce bladder

cancer in animals (24) and were removed from

commerce in 1969. OTA (282) reviewed data

that show saccharin caused cancer of the bladder in rats in two circumstances: 1) in

straightforward feeding studies when given over

two generations, and 2) when given following

the administration of a powerful carcinogen.

OTA also reported positive and negative results

from a number of short-term tests. Therefore,

some evidence supports the conclusion that saccharin causes cancer in defined conditions. The

human evidence that has been collected over the

last few years fails to distinguish clearly between saccharin and cyclamates, but it is more

relevant to the former as the use of saccharin

began earlier (in 1902) and has continued

longer. An increase in incidence or mortality

from bladder cancer could not be attributed to

the introduction of saccharin (16).

One epidemiologic study (175) showed that

ingestion of artificial sweeteners by males increased their relative risk of bladder cancer to

1.6. (The incidence of bladder cancer among

men who did not consume saccharin was taken

as relative risk equal to 1.0; saccharin users had

a risk 60-percent higher). The results reported in

the study were consistent with those from the

laboratory. In both cases cancer occurred in the

bladder in males.

Subsequent epidemiologic studies have failed

to confirm the relative risk of 1,6. The large

case-control study of bladder cancer in the

United States conducted by NCI revealed relative risks of 0.99 for males and 1.01 for females

among users of artificial sweeteners in any form

(174). However, Wilson (362) points out that

one projection from animal studies suggests that

only about 500 bladder cancer cases annually

are to be expected from saccharin consumption

in the United States (see also 282). The relative

risk represented by 500 cases could not have

been detected in the case-control study.

Doll and Peto (93) reviewed five case-control

studies which examined saccharin consumption

and bladder cancer. With the exception of Howe

et al. (175), the relative risks in all the experiments lie very close to 1.0; some slightly higher;

some lower. They conclude that the “human

evidence could hardly be more null, ” at least for

cancer of the bladder, which was the anatomic

site affected by saccharin in rats (93).

BHT has been used extensively as an antioxidant for many years. It is not carcinogenic by

itself, but has been reported to enhance the production of lung tumors by urethan in mice (93).

Conversely, its antioxidant effect is found to inhibit the formation of active carcinogens in the

laboratory (93), and similar effects might be expected to occur in vivo. It has been postulated

that its use— and perhaps that of the more widely used butylated hydroxyanisole—have contributed to the decline in mortality from stomach cancer (24).

Nitrites have been used to preserve meat since

the last century (also see above). According to

Shubik (328), nitrites added to food Constitutes

only 10 percent of the total nitrite reaching the

stomach in vegetables and saliva. However, if

the formation of nitrosamines and nitrosamides

in the intestinal tract proves to be of practical

importance, dietary nitrite may play a role in

cancer formation. The National Research Council’s Panel on Nitrates (cited in 93) was unable to

reach any conclusions about their quantitative

effect, but advised that reasonable measures be
taken to minimize human exposure to N-nitroso

compounds, including the restriction of the

amounts of nitrate and nitrite added to meat

products.

There is great uncertainty regarding the contribution of the compounds discussed above to

the formation of cancer. The possibility also exists that other additives might have detrimental

effects.

Diet Summary

Dietary components discussed above, and

many others, are currently the subjects of intensive research, from which some results should

be known within the next few years. The outcomes may show diet to be a factor in determining cancer occurrence at many sites, particularly

the stomach, large bowel, endometrium, gallbladder, and in tropical countries, the liver.

Diet may also be shown to affect the incidence

OCCUPATIONAL EXPOSURES

The last several years have seen a heated discussion concerning the contribution of occupational exposures to cancer in the United

States. Since the formation of the Occupational

Safety and Health Administration (OSHA) in

1970, 20 regulations have been promulgated and

two more proposed relating to suspect carcinogenic factors in the workplace. Labor unions

and public interest groups have criticized OSHA

for moving slowly, while industry and their

trade associations claim unnecessary irrational

regulation and undue expense. In an effort to

implement a comprehensive and rational policy

for the regulation of carcinogens in the workplace, OSHA held 2 months of hearings in 1978

which attracted the participation of labor

unions, environmental groups and spawned a

major new trade association, the American Industrial Health Council (AIHC). Subsequently,

OSHA promulgated “a general policy for the

identification and regulation of physical and

chemical substances that pose a potential occupational carcinogenic risk to humans”

(278,279).

of cancers of the breast and pancreas, and,

through the antipromoting effects of retinoids,

to reduce incidence of epithelial cancers in many

other tissues. If these or other hypotheses are

proven, practicable means of dietary modifications may eventually be identified to reduce cancer rates.

Cairns (43) draws attention to the probable

difficulty of changing cancer incidence even if a

direct link is shown between a diet constituent

and cancer incidence:

Cancer of the lung is due to a pleasant and

highly addictive habit, cancer of the large intestine and breast are most common in affluent

countries and so are presumably associated with

some desirable habit, such as a diet high in animal fats, that the rich nations can afford and the

others cannot . . . . These are signs, therefore,

that the campaign to prevent cancer may come

into some conflict with people’s immediate

desires.

The first recognized industrial cancer was

identified by Percival Pott, a British surgeon,

who observed that scrotal cancer occurred more

frequently in men who had been employed as

chimney sweeps as boys. This led to the identification of soot as the first chemical and occupational carcinogen. In the ensuing years,

many other groups of workers have been found

to suffer from occupationally induced cancer.

For the purpose of this assessment, occupational

exposure is defined as exposure to a substance

or physical agent through any route during the

course of employment.

The workplace setting has proved to be the

single most productive source of information in

the discovery of carcinogenic substances. This is

because of the defined populations involved and

higher exposures which can be more easily

monitored and identified. Table 17 lists carcinogens and processes found in the workplace

which are associated with increased cancer risk.

Occupations known to produce an elevated risk

of cancer, though the specific agents responsible
Ch. 3—Factors Associated With Cancer ● 85

Table 17.—Occupational Cancer Hazards

Agent

Acrylonitrile

4-aminobiphenyl

Arsenic and certain arsenic

compounds

Asbestos

Auramine and the manufacture

of auramine

Benzene

Benzidine

Beryllium and certain beryllium

compounds

Bis(chloromethyl) ether (BCME)

Cadmium and certain cadmium

compounds

Carbon tetrachloride

Chloromethyl methyl ether

(CM ME)

Chromium and certain

chromium compounds

Coal tar pitch volatiles

Coke oven emissions

Dimethyl sulphate

Epichlorohydrin

Ethylene oxide

Hematite and underground

hematite mining

Isopropyl oils and the

manufacture of isopropyl oils

Mustard gas

2-naphthylamine

Nickel (certain compounds)

and nickel refining

Polychlorinated biphenyls

(PCBs)

Radiation, ionizing

Radiation, ultraviolet

Soots, tars, mineral oils

Thorium dioxide

Vinyl chloride

Agent(s) not identified

Cancer site or type —

Lung, colon

Bladder

Lung, skin, scrotum, lymphatic

system, hemangisarcoma of the

liver

Lung, larynx, GI tract, pleural and

peritoneal mesothelioma

Bladder

Leukemia

Bladder, pancreas

Lung

Lung

Lung, prostate

Liver

Lung

Lung, nasal sinuses

Lung, scrotum

Lung, kidney, prostate

Lung

Lung, leukemia

Leukemia, stomach

Lung

Paranasal sinuses

Respiratory tract

Bladder, pancreas

Nasal cavity, lung, larynx

Melanoma

Skin. pancreas, brain, stomach,

breast, salivary glands, thyroid,

GI tract, bronchus, Iymphoid tis-

———. —.

— A .

— .

— —Type of workers exposed — — —

Manufacturers of apparel, carpeting, blanket% draperies. synthetic

furs, and wigs

Chemical workers

Workers in the metallurgical industries, sheep-dip workers, pesticide

production workers, copper smelter workers, vineyard workers, insecticide makers and sprayers, tanners, miners (gold miners)

Asbestos factory workers, textile workers, rubber-tire manufacturing

industry workers, miners, insuIation workers, shipyard workers

Dyestuffs manufacturers, rubber workers, textile dyers, paint

manufacturers

Rubber-tire manufacturing industry workers, painters, shoe manufacturing workers, rubber cement workers, glue and varnish workers,

distillers, shoemakers, plastics workers, chemical workers

Dyeworkers, chemical workers

Beryllium workers, electronics workers, missile Parts producers

Workers in plants producing anion-exchange resins (chemical

workers)

Cadmium production workers, metallurgical workers, electroplating

industry workers, chemical workers, jewelry workers, nuclear

workers, pigment workers, battery workers

Plastic workers, dry cleaners

Chemical workers, workers in plants producing ion exchange resin

Chromate-producing industry workers, acetylene and aniline worker%

bleachers, glass, pottery, pigment, and linoleum workers

Steel industry workers, aluminum potroom workers, foundry workers

Steel industry workers, coke plant workers

Chemical workers, drug makers, dyemakers

Chemical workers

Hospital workers, research lab workers, beekeepers fumigators

Miners

Isopropyl oil workers

production workers

Dyeworkers, rubber-tire manufacturing industry workers, chemical

workers, manufacturers of coal gas, nickel refiners, copper smelters,

electrolysis workers

Nickel refiners

PCBs workers

Uranium miners, radiologists, radiographer% luminous dial Painters

SOUFiCES; Institute of Med!clne (179),

sue, leukemia, multiple myeloma

Skin Farmers, sailors, arc welders

Skin, lung, bladder, GI tract Construction workers, roofers, chimney sweeps, machinists

Liver, kidney, larynx, Ieukemia Chemical workers, steelworkers, ceramic makers, incandescent, lamp

makers, nuclear reactor workers, gas mantle makers, metal refiners,

vacuum tube makers

Liver. brain, lung, hematolympho- Plastics factory workers, vinyl chloride polymerization plant workers

‘poietic system; breast

Pancreas

Stomach

Brain, stomach

Hematolymphopoietic system

Bladder

Eye, kidney, lung

Leukemia, brain

Colon, brain

Esophagus stomach, lung

Chemists

Coal miners

Petrochemical industry

Rubber industry workers

printing pressmen

Chemical workers

Farmers

Pattern and model makers

Oil refinery workers

— ———-.—— ———

‘International Agency for Res;a~cF~~ C-anc~r (185), and the Occupational SafetY and

———— Health Administration (279a)
86 ● Technologies for Determining Cancer Risks From the Environment

have not yet been identified, are also included.

Many of these exposures represent substantial

hazards, and it is likely that other human carcinogens exist which have not yet been detected

in the workplace. This may be because the

added cancer risk is small in comparison to

other causes of cancer, because only a few

workers have been exposed, or simply because a

hazard has not been suspected and therefore not

looked for. Besides the substances listed, many

other industrial chemicals have been found to

cause cancer in laboratory animals. It must also

be borne in mind that human cancer seldom develops until one or more decades after exposure

to a carcinogen, and thus it is too early to ascertain whether chemicals introduced into industry

during the last few decades will affect cancer

rates.

Epidemiologically demonstrating an increased risk of developing cancer from an occupational exposure generally involves results

from examining large numbers of exposed people, the existence of relatively large risks, or

sometimes a rare cancer, which facilitates drawing associations. Even then, years may pass

before a hazard is identified. As the workplace

changes, workers will be exposed to additional

substances, some of which may turn out to be

carcinogenic.

Estimating the proportion of today’s cancers

that can be attributed to occupational hazards is

difficult. Determining how many future cancers

may arise from past and present occupational

exposures is even more speculative. As with all

studies of carcinogenesis, the latent period

makes it extremely problematic to associate a

particular occupational exposure with an increased cancer risk. Individuals frequently

change jobs which can result in exposure to

numerous substances, several of which may interact with each other either to promote or to inhibit tumor formation. With rapidly changing

technologies, new exposures emerge while

others cease. Often, the available information is

based on studies which have inadequate exposure information. Exposure data are generally

poor because they are usually not collected until

a hazard is recognized, or at least suspected.

OSHA requires monitoring only for some of the

substances which it regulates. Oftentimes employees, and even in some cases employers, are

unaware of specific chemical exposures.

Certain occupational diseases are difficult to

diagnose and this can lead to underreporting, as

exemplified by recent letters to the New England

Journal of Medicine concerning the inability of

board-certified pathologists to identify cases of

asbestosis (1,318). Studies can be designed to

obtain exposure data and continuously monitor

workers’ health, but they are expensive. Even

though no system has yet been adopted to

gather these types of information, such an approach may be feasible in some industries.

Many estimates have been made of the percentage of human cancers associated with occupational exposures, most ranging from 1 to 10

percent. In most instances the bases for these

estimates are not presented and the estimates

themselves appear little more than informed

guesses. Since epidemiologic studies do not

always follow individuals for their full lifetimes,

calculated risks may be underestimates. The

magnitude of a detected risk is dependent upon

the time elapsed between exposure and the time

individuals are studied.

Higginson and Muir (165) estimated the impact of environmental factors in human cancer.

They stated:

Although occupational cancers recognized so

far provide some of the most satisfactory data

for identifying external agents, the absolute

number of cancers due to occupational exposures would appear to be relatively small, probably 1 to 3 percent of all cancers.

Wynder and Gori (368) estimated the percent

of 1976 cancer incidence in the United States attributable to occupation, From their summary

figure, it appears that they estimated that the

fraction of cancers attributable to occupational

factors was 4 percent for men and 2 percent for

women. Their explanation for these estimates is

as follows:

The data presently available are, at best, educated estimates of the relationship between

specific cancers and specific occupational

groups. Cole et al.2 (1972) suggested that 20%

2P. Hoover, R. Cole, and G. H. Friedell, “Occupation and Cancer of the Lower Urinary Tract, ” Cancer 29: 1250-60, 1972.
Ch, 3–Factors Associated With Cancer 87

of bladder cancers occurring in males in the

Boston area are related to occupational exposure. In certain counties of New Jersey, the increased risk for this cancer appeared to be high

among workers in certain chemical industries.

General estimates of the percentage of all human

cancers related to occupational exposure range

between 1 and 10 percent.

Cole (62) estimated slightly higher figures for

workplace-caused cancer:

My estimates are less than 15 percent for men

and less than 5 percent for women. These rather

low figures emphasize that we are not dealing

with a single major public health problem.

Rather, we are dealing with a series of modest

problems which are, however, of great importance in the specific industries where they occur,

Cole does not describe the data used to derive

the estimate.

Higginson and Muir (166), in a later study

estimated that 6 percent of male cancers, skin

cancer included, in the Birmingham and West

Midland region of England in 1968 through

1972, could be attributed to occupational exposures. Their paper describes some of the information considered.

Fox and Adelstein (126) reviewed 1970-72

British vital statistics and found that 12 percent

of the differences in cancer mortality among different occupational classifications could be explained by variations associated with work and

the remaining 88 percent by lifestyle factors.

They describe their estimate as an “oversimplified calculation, ignoring interactions between direct and indirect influences . . . clearly

very crude. ”

Recently, a different approach was used to

generate an estimate of workplace cancers by 10

distinguished research workers of NCI, the National Institute of Environmental Health Sciences, and the National Institute for Occupational Safety and Health (82). The report calculated the proportion of cancers “for the near

term and future, ” from quantitative estimates of

risk and the numbers of workers exposed to six

known carcinogens—asbestos, arsenic, benzene, chromium, nickel oxides, and petroleum

fractions. This paper (82) concludes:

Reasonable projections of the future consequences of past exposure to established carcinogens suggest that . . . occupationally related

cancers may comprise as much as 20% or more

of total cancer mortality. Asbestos alone will

probably contribute up to 13-18% and the data

(relating to five other carcinogens) suggest at

least 10-2070 more.

The total of occupationally related cancers from

those six exposures is then 23 to 38 percent of

the overall cancer total, to which must presumably be added the effects of other occupational carcinogens not included in the calculation. This report has been widely misquoted as

an assessment of the contribution of occupational exposures to present cancer rates and is

frequently discussed and criticized because of

the magnitude of the estimates and their divergence from previous estimates.

While this report has not been submitted for

publication, it has been widely circulated and

reviewed (c f., 9,93,332,345). The two reviews

that have been published are discussed below.

Toxic Substances Strategy Committee

(TSSC) Review

TSSC (345) identified several methodological

aspects which might have caused the HEW (82)

paper to overestimate or to underestimate the

contribution of occupational factors to the overall cancer rate.

Overestimating

1.

2.

3.

The number of cases of lung cancer associated with asbestos may have been overestimated by attributing all cases of lung cancer among asbestos workers to asbestos exposure.

Exposures to the examined carcinogens were

probably higher in the past than they have

been recently.

Estimates of the number of workers exposed

may have been too high since: a) workers

who were employed in more than one of the

six industries, a likely possibility in the

chromium and nickel industries, might have

been counted twice, and b) estimates of the
88 ● Technologies for Determining Cancer Risks From the Environment

number of exposed persons still alive and thus

at risk may be exaggerated. This is particularly so with regard to the asbestos industry.

Underestimating

1. The six industries examined are not the only

ones believed to have carcinogens in the

workplace.

2. Epidemiologic data on which the estimates

are based do not reflect total lifetime risk.

3. Identifying unexposed groups to use for comparison is difficult and the comparison group

used may be at a higher risk then the least exposed members of the population.

The TSSC report concludes (345):

Because it is difficult to quantify the impact of

all these factors, one cannot tell whether the factors which lead to overestimation and those

which lead to underestimation balance each

other out.

Doll and Peto Review

Doll and Peto (93) examined the calculations

in the OSHA paper and in their view, the estimates:

. . . could not be regarded as having any validity, primarily because the implicit assumption

was made that the industrial conditions that had

been recognized as giving rise to gross hazards of

occupational cancer were typical of the condition to which 11.9 million workers in the United

States were currently exposed.

Doll and Peto (93) used a different approach

to estimate the proportion of cancers associated

AIR AND WATER POLLUTION

Determining the health effects of pollution is

difficult, particularly from low-level chronic exposures. The absolute risk from each pollutant

is likely to be low and the resulting disease may

not appear for many decades, as is the case with

cancer. Direct measurement of the incremental

risk from these pollutants using epidemiologic

methods, against the background of more potent carcinogens, for instance tobacco, presents

with occupational exposures. Rather than focusing on individual occupational hazards, they

based their assessment on the contribution of

occupational factors to individual cancer sites

and arrived at an estimate of approximately 4

percent with an acceptable range from 2 to 10

percent.

Lung cancers caused by asbestos contribute

the largest proportion to the estimates made

both by Doll and Peto (93) and by HEW (82).

Hogan and Heel (171) have completed a careful

analysis of asbestos and cancer and conclude

that it may be associated with as much as 3

(range: 1.4 to 4.4) percent of all cancers now or

likely in the near future. This inference is considerably less than the 13 to 18 percent estimated by HEW (82).

Occupational Exposure Summary

Despite all of the arguments that have surrounded the estimates of workplace associated

cancers, almost every estimate fits comfortably

in the range of 10 & 5 percent. Uncertainties

about unknown carcinogens confound the estimates. Regardless of the exact number of

cancers associated with the workplace, the identification of causes is most important. Preventive measures can reduce exposures only to

identified risks. Recently, an unusual number of

melanomas in a nuclear research installation

(89) and of brain tumors among oil industry

workers (55) have triggered further studies.

These examples emphasize the value of workplace monitoring.

extreme methodological problems. There is

often little variation between individuals in the

type and extent of exposure to pervasive pollutants, and where measurable differences do exist,

confounding variables often hinder adequately

demonstrating an effect or the lack of one. It is

therefore often necessary to rely on indirect

sources of evidence that a pollutant is carcinogenic: short-term laboratory experiments that
Ch. 3—Factors Associated With Cancer ● 89

demonstrate mutagenicity or other toxic effects,

animal bioassays, and epidemiologic data derived from groups exposed to high levels of pollutant chemicals. The latter are often obtained

in special situations, usually occupational,

where people are exposed to much larger

amounts than the general public.

Air Pollution

Air pollution is primarily a problem of major

cities but it can move in and out of different

areas and affect everyone. The Census Bureau

(35) estimates that over 70 percent of the U.S.

population lives in urban centers and that this

number is increasing with each passing year.

The amount and type of air pollution in a given

region changes not only with the time of day,

but from day to day and year to year, making

meaningful measurement difficult. Air pollution

can be generally classified as a secondary environmental stressor, aggravating existing disease conditions or increasing the risk of disease

in those predisposed to ill health (326).

A variety of carcinogenic substances has been

identified in air—e. g., asbestos, arsenic, PAH—

and EPA has promulgated several regulations

under section 112 of the Clean Air Act to limit

exposure to these substances. Table 17 (see Occupational Exposures) lists several recognized

occupational carcinogens which may escape

into the atmosphere in the course of industrial

activity and constitute a potential cancer

hazard.

Morbidity and mortality due to chronic obstructive lung disease—asthma, bronchitis, and

emphysema —are probably the most important

long-term health effects of air pollution. Urban

areas generally have a higher death rate from

chronic obstructive lung disease and lung cancer

than more rural environments (54,205). This

has been used as the basis for suggesting that atmospheric pollution is an etiologic factor in the

development of cancer. However, like many apparently simple observations, this one is

plagued by conflicting and confounding factors.

Individuals residing in urban centers generally

have smoking, drinking, and eating habits different from their rural counterparts, and their

risk of infection and exposures to industrial environments also varies. In addition, urban areas

tend to have more accurate death certification

and disease diagnosis which might bias collected

statistics. Epidemiologic studies that examine

the health effects of air pollution must deal with

these factors.

Many airborne carcinogens are believed to interact synergistically with tobacco and occupational exposures. Since cigarette smoking is the

predominant cause of lung cancer, it is a primary suspect for explaining the observed urban/rural gradient. There have been numerous

attempts to disentangle the health effects of

smoking from environmental pollution. Unfortunately, many studies have compared broad

categories of smoking habits, such as “smokers”

versus “nonsmokers” or “never smoked” versus

“ever smoked” which reduces the probability of

discerning any effects. More specific categories —e.g., taking into account number of years

smoked, age at which smoking began, number

of cigarettes smoked per day—are necessary to

evaluate any urban/rural variation. In addition,

other important differences may exist in smoking habits between urban and rural dwellers, for

instance, in the tar and nicotine content, inhalation habits, and other factors contributing to

differences in effective dose of carcinogen

received (see Tobacco). Most studies concentrating on nonsmokers have failed to demonstrate, or found only a slight difference, in lung

cancer rates between nonsmokers in urban and

rural environs, suggesting that airborne carcinogens by themselves can be responsible for only a

small portion of the disease. Several have suggested that the effects of smoking a given

amount may be greater in urban than rural

areas (for review, see 91).

One of the most extensive investigations into

the effects of air pollution is a cohort study conducted by ACS. Data concerning men without

known carcinogenic occupational exposure produced “little or no support to the hypothesis that

urban air pollution has an important effect on

lung cancer death rates” (154). When lung

cancer rates for men with occupational exposure

were compared to those for men without occu2 ,_+ ~ 1

 -

- 1? 1 - -
90 ● Technologies for Determining Cancer Risks From the Environment

pational exposures, the authors found a relative

difference of 26 percent in large metropolitan

areas, 18 percent in smaller metropolitan areas,

and 7 percent in nonmetropolitan areas. These

differences, as Hammond and Garfinkel suggest, may be due to different types of occupational exposures in the different areas. However, an alternative explanation is that the

higher ratio of lung cancer maybe due to an attribute of the place of residence, air pollution

being one possible factor. In a reevaluation of

these data, it was estimated that approximately

10 percent of lung cancer in the ACS population

could be attributed to an “urban effect” after accounting for smoking and occupation (61).

Studies which concentrate on nonsmokers or the

nonoccupationally exposed do not permit investigating any interactive effects.

Another method for estimating the influence

of pollution on the cancer rate is to extrapolate

from instances of high exposure. Occupational

studies that include measurements of the concentration of carcinogens in the respired air are

especially useful for this purpose. Measurements of the concentration of B(a)P are frequently used because it appears to be a good indicator of the concentration of PAH. However,

it should be noted that B(a)P is not a perfect indicator of PAH in air, nor does it accurately

reflect the carcinogenic potential of total air

pollution. For instance, some non-PAH fractions of air pollution are as active as PAH in

causing changes in cell cultures, which is a

measure related to carcinogenicity (294).

Pike and his colleagues (294) concluded that 1

ng B(a)P per m3 in city air causes 0.4/100,000

extra cases of lung cancer per year. In 1977, an

international symposium at the Karolinska Institute in Stockholm, reached a similar conclusion (54):

. . . combustion products of fossil fuels in ambient air, probably acting together with cigarette

smoke, have been responsible for cases of lung

cancer in large urban areas, the numbers produced being of the order of 5 to 10 cases per

100,000 males per year . . . The actual rate will

vary from place to place . . . depending upon

local conditions.

These estimates must be used with caution since

they are directly dependent on the concentration

of the different air pollutants, many of which

have been changing over time. In 1959, BaP

concentrations ranged from 1 ng/m3 to approximately 60 ng/m3

; most nonurban areas had

levels below 1 ng/m3

. Recent monitoring by

EPA found that the average concentration of

B(a)P in 26 urban areas decreased from approximately 4 ng/m3 in the late 1960’s to 0.5 ng/m3 in

1977 (70). Doll and Peto (93) estimated that the

current contribution of atmospheric B(a)P and

associated combustion products to the production of lung cancer is unlikely to account for

more than 1 percent of future cases of lung

cancer.

Similar calculations have been made for other

carcinogenic substances including airborne arsenic and asbestos (93). These suggest that contributions to the overall cancer rate from these

agents should be small. Higher levels of pollutants and therefore greater risk may exist around

particular sources of pollution as exhibited by

the significantly increased mortality from lung

cancer found in residents of counties with copper, lead, or zinc smelters or refineries (28). The

amount of asbestos commonly present in urban

air is 1,000 to 10,000 times less than the most

stringent occupational regulations, although the

general public is exposed continuously to this

low level. At present, there is no evidence to indicate that the risk to the general public from

these sources is measurable.

Also included under the heading of atmospheric pollution is the effect on the general population of mining and milling of uranium and

other radioactive ores and of radioactive fallout

due to testing of nuclear weapons. The HEW Interagency Task Force on the Health Effects of

Ionizing Radiation (182) estimated that for 1978

the U.S. population collective dose was 1 million to 1.6 million person-rem. Based on the risk

estimates derived from the linear model of the

NAS Committee on the Biological Effects of

Ionizing Radiation (BEIR) III (158 to 403 excess

cancer deaths per million persons from continuous lifetime exposure to 1 rad/yr) one can estimate that atmospheric radiation accounts for
Ch. 3—Factors Associated With Cancer ● 91

an upper limit of 645 fatal cancers per year. The

lower limit of risk can be considered to approach zero.

The other class of atmospheric agents given

considerable attention because of a potential effect on cancer rates are the chlorofluorocarbons. Chlorofluorocarbons, used extensively

as refrigerants and aerosol propellants, persist

in the atmosphere and, it is argued, eventually

reach the stratosphere where they react with

ozone, reduce its concentration, and hence permit more ultraviolet light to reach the surface of

the Earth. This occurrence would result in an increase in the incidence of skin cancer, including

melanoma. The issues involved, which are complex and based on a number of unproved

assumptions about physical and chemical processes, have been reviewed by the National

Academy of Sciences (NAS) (70,264). They

found that if global release of chlorofluorocarbons were to continue at 1977 rates, the

ozone concentration would eventually decline

by 16.5 percent, with a reduction of about 8 percent by the year 2030 (70). A 16-percent ozone

depletion is predicted to eventually cause

several thousand more cases of melanoma each

year in the United States and several hundred

thousand more cases of other less serious skin

cancers (70). This is approximately the same

order of magnitude predicted by Urbach (354).

The present contribution of chlorofluorocarbons to overall cancer incidence is likely to be

much less.

Until recently, air pollution was a problem

believed to be limited to outside air or dirty

workplaces. Several studies have found that indoor air pollution may be a more serious health

hazard than outdoor air pollution (140). It has

been shown that a single smoker can pollute indoor air with around 1-1.5 ng/m3 B(a)P (260).

NAS was asked by EPA to examine the variables which are contributing to indoor air pollution, their sources, and possible health hazards.

To date, this issue has not been looked at in a

systematic way though many people spend a

large percentage of their time in the indoor environment. The General Accounting Office

(140) suggested that the Clean Air Act be

amended to provide EPA the responsibility and

necessary authority to address indoor air pollution in the nonworkplace.

In sum, determining the proportion of the

total cancer rate attributable to air pollution is

not possible with the available data. In most

studies, air pollution and smoking are seen as

interactive in cancer production. Whatever the

correct percentage of cancer associated with air

pollution, most researchers in this area believe

that it is small. Doll and Peto (93) estimated that

2 percent of cancer mortality, representing approximately 8,000 cancer deaths, can be attributed to industrial pollution of air, water,

and food, principally accounted for by the uncertain effects of combustion products of fossil

fuels in urban air. This relatively small percentage does not mean that efforts to control air

pollutants should be minimized. Air pollution is

responsible for many serious detrimental health

effects other than cancer and uncontrolled pollution might someday be found to impact more

dramatically on cancer rates. Greater attention

should be directed at discerning whether atmospheric pollutants act as initiating and/or promoting agents. If air pollution is acting as a secondary stressor, then its role as a promoter may

prove to be most important.

Drinking Water Pollution

The extent to which water pollution is a

causative agent for cancer is even less certain

and more debated than is the role of air pollution. The passage of the Safe Drinking Water

Act, Public Law 93-523, December 1974, was

prompted by the recognition that organic and

inorganic chemicals, including substances identified as known or suspect carcinogens and mutagens were present in drinking waters. The

sources for these contaminants are numerous:

industrial pollution, agricultural runoff, leachate from waste disposal sites, and of particular

recent interest, byproducts of the disinfection of

drinking water.

In the mid 1970’s, EPA set up various programs, such as the National Organics Reconnaissance Survey, to evaluate the nature and extent of organics in drinking water. Primary em-
92 ● Technololgies for Determining Cancer Risks From the Environment

phasis was on detecting a class of organics, the

trihalomethanes, formed during water treatment with chlorine and believed to be the most

ubiquitous group of organics found in drinking

water. Levels have been found to range from

below 1 ug/liter to above 300 ug/liter. The

Federal Government has recently sought to

reduce exposure to trihalomethanes by promulgating a regulation establishing a “maximum contaminant level” of 100 ug/liter total

trihalomethanes for all community water systems serving 10,000 persons or more that add a

disinfectant in the treatment of their water

(107).

Much attention has been centered on the relatively high concentrations of synthetic organics found in untreated drinking water from

ground water sources in certain areas of the

United States. The extent to which these waterborne pollutants contribute to human carcinogenesis has been evaluated by the examination

of both laboratory and epidemiologic data.

Many of these studies were reviewed by the

NAS Safe Drinking Water Committee (266,270)

as mandated by the Congress. (These reports

stand as references for many issues concerning

the health effects of drinking water contaminants. )

The numerous epidemiologic studies that

have examined the association between drinking

water and cancer have been of varying reliability and have taken many forms. These studies

suggest an association between constituents in

drinking water and cancer mortality (169).

However, the degree and extent of the association is disputed. NAS discussed and evaluated

10 of the studies which focused on the relationship of trihalomethanes and cancer mortality.

All but one of the studies were found to demonstrate a statistical association between exposure

and excess cancer rate, but excess cancer at no

single anatomical site was associated with exposure. The epidemiologic analyses do not have

the extrapolation difficulties of animal experiments, but they are plagued by confounding

variables such as exposures to other sources of

carcinogenic stimuli, including smoking, which

were generally not accounted for. Many of the

studies utilized the cancer deaths rates of a

region and related them to the water quality of

that region. The difficulty with this approach is

twofold: 1) an individual’s place of death may

differ considerably from where that person

resided during most of his water-drinking life,

and 2) the data on water quality are extremely

limited, often reflecting the water quality of

only one water source in a region.

Prior to 1970, about 100 different organic

compounds has been identified in water (169).

In the past, organic pollutants were measured

by crude, nonspecific methods such as biochemical oxygen demand and total organic content.

Today, analytical techniques permit detection

of chemicals in minute quantities, and many are

found in concentrations of parts per trillion.

NAS (270) found that over 700 volatile organic

compounds contaminate U.S. drinking water.

Volatile substances make up only 10 percent of

the total organic content of water and approximately 90 percent of this component has been

identified and quantified. On the other hand,

only 5 to 10 percent of the nonvolatile constituents of drinking water have been characterized

(266). As technology improves and detection

methods become more sensitive, an ever-increasing number of compounds may be detected

in drinking water.

In a report for the Council on Environmental

Quality, Crump and Guess (74) reviewed five of

the recent case-control studies on cancer risk

associated with drinking water quality in this

country. While inadequacies were identified in

each of the studies (74):

. . . increased risks . . . are large enough to be

of concern yet small enough to be very difficult

to separate from confounding risks associated

with other environmental factors.

Rectal cancer risk ratios for chlorinated v. unchlorinated water were found to range from

1.13 to 1.93. In three of the studies the risk

ratios were statistically significant. Statistically

significant risk ratios were also found in three of

the studies for colon cancer and in two studies

for bladder cancer. Although the studies did not

indicate a consistently increasing cancer risk

with increasing exposure to organic contaminants, one study did show such a relationship
Ch. 3—Factors Associated With Cancer ● 93

for rectal cancer and another was suggestive for

colon cancer.

Crump and Guess made crude estimates of

the possible range of carcinogenic risks from

consuming ground water (from wells) containing various levels of synthetic organic chemicals. They computed an upper risk limit of 7.5

x 10-4 or about one case per 1,300 persons

from consuming water from a hypothetical well

containing the highest detected concentrations

of commonly found contaminants. Levels to

which most Americans are exposed are typically

much lower. The estimate is based on summing

the individual upper limits on human risk derived by a procedure which tends to produce exaggerated estimates of human risk. On the other

hand, only risks from chemicals known to be

present in the wells and for which positive carcinogenicity data exist, were considered in the

estimate (74). Crump and Guess also computed

an upper limit on the lifetime total cancer risk

associated with an average concentration of

chloroform to be 1.8 x 10-4 or about one case

per 5,000 persons. The actual risk is probably

much lower.

The NAS Safe Drinking Water Committee

lists 19 carcinogens and 3 suspected carcinogens

identified in or thought to be in drinking water

(266). NAS estimated the 95-percent upper confidence limit of cancer risks to humans from

lifetime exposure to water containing 1 ug/1 of

each of these compounds. These estimates are

displayed in table 18 and are compared with risk

estimates computed by EPA’s Carcinogen Assessment Group. It is interesting to note that in

many cases a tenfold to hundredfold difference

exists between the two estimates. These differences are due to the use of different extrapolation models and the use of point rather than interval estimates.

The problem of evaluating the effects of multiple exposures is acutely relevant to waterborne pollutants because of the multitude of

compounds found in drinking water. Bioassays

have rarely attempted evaluation of synergistic

or antagonistic effects. Therefore, these estimates may not accurately reflect the human carcinogenic risk from these compounds.

Table 18.—Concentration of Drinking Water

Contaminants and Calculated Excess Cancer Risk

NASa CAGb

1 0 -

6

1 0 -

6

Ug/lc Ug/lc

Acrylonitrile . . . . . . . . . . . . . . . .

Arsenic . . . . . . . . . . . . . . . . . . . .

Benzene . . . . . . . . . . . . . . . . . . .

Benzo (a) pyrene. . . . . . . . . . . . .

Beryllium . . . . . . . . . . . . . . . . . .

Bis (2-chloroethyl) ether . . . . . .

Carbon tetrachloride. . . . . . . . .

Chlordane. . . . . . . . . . . . . . . . . .

Chloroform . . . . . . . . . . . . . . . . .

DDT . . . . . . . . . . . . . . . . . . . . . . .

1,2-Dichloroethane . . . . . . . . . .

1,1-Dichloroethylene . . . . . . . . .

Dieldrin . . . . . . . . . . . . . . . . . . . .

Ethylenedibromide . . . . . . . . . .

ETU . . . . . . . . . . . . . . . . . . . . . . .

Heptachlor . . . . . . . . . . . . . . . . .

Hexachlorobutadiene . . . . . . . .

Hexachlorobenzene . . . . . . . . .

N-nitrosodimethylamine. . . . . .

Kepone . . . . . . . . . . . . . . . . . . . .

Lindane. . . . . . . . . . . . . . . . . . . .

PCB . . . . . . . . . . . . . . . . . . . . . . .

PCNB . . . . . . . . . . . . . . . . . . . . .

TCDD . . . . . . . . . . . . . . . . . . . . . .

Tetrachloroethylene . . . . . . . . .

Trichloroethylene . . . . . . . . . . .

Vinyl chloride . . . . . . . . . . . . . . .

0.77—

—

—

—

0.83

9.09

0.056

0.59

0.083

1.4—

0.004

0.11

0.46

0.024 —

0.034 —

0.023

0.108

0.32

7.14—

0.71

9.09

2.13

0.034

0.004

3.0—

0.02—

0.086

0.012

0.48—

1.46

.28—

0.0022 —

2.4

1.4—

0.0052 —

—

—

—

5.0 x 10-’

0.82

5.8

106.0

astandardized to 1O-S risks from Natfonal Academy of Sciences, Drinking Water

and Health (266) for consumption of 1 I/water/day

bReca[culated to exclude aquatic food Intake from Cancer Assessment Group,

Arnbent Water (Jua//ty Cr/ter/a (104) Standardized to 1 I/water/day Intake

cAverage adult water consumption IS 2 I/day.

SOURCE Office of Technology Assessment

As more chemicals are tested, additional substances found in drinking water will be shown

to be carcinogenic. Two substances identified in

drinking water, toxaphene and 1,2 dichloroethane, not considered carcinogenic by NAS in

1977, have since been shown by NCI to be carcinogenic in animals. Two additional compounds, bromodichloromethane and chlorodibromomethane, found in most drinking water

systems surveyed by EPA, have not been appropriately tested for carcinogenic properties but

have been shown to be mutagenic in the Ames

test (169). In 1978, NCI (203) published a list of

23 recognized or suspected carcinogens, 30

mutagens and 11 tumor promoters which have

been found in American drinking water.

Turning from the organics to inorganic, several studies have attempted to correlate levels of
94 ● Technologies for Determining Cancer Risks From the Environment

carcinogenic trace metals in water supplies, with

cancer rates. Associations of high levels of arsenic in drinking water with cancer of the skin and

other sites were found in Taiwan and Argentina

(203,370). Berg and Burbank (25) compared

concentrations of eight carcinogenic metals in

water supplies with State cancer mortality rates.

They found strong correlations with cadmium

concentrations and cancer mortality; no significant correlations with iron, cobalt, and chromium; a low but not biologically interpretable

level of significance with nickel and arsenic; and

some correlations with lead and beryllium

which correspond to known biological activities.

Asbestos, an established human carcinogen,

is also of some concern since it has been found

to contaminate water supply systems. No relationship between asbestos in drinking water and

cancer has been found but available data are

very limited.

Experimental and epidemiologic data provide

some evidence that a carcinogenic hazard exists

from drinking water contaminants, but does not

permit adequate quantification. Most attention

CONSUMER PRODUCTS

Consumer products are a class of agents that

are so numerous that it is only possible to echo

the uncertainty with which pollutants were discussed in the previous section. Detergents and

other surfactants, hair dyes and other cosmetics, solid or foam plastics, paints, dyes,

polishes, solvents, fabrics, and even the processed paper and the printer’s ink in this report

are but a few. It is likely that some of these

products are already causing, unnoticed, a number of today’s cancers, and it is quite possible

that after prolonged exposure substantial risks

might be detected in the future.

The difficulty in assessing cancers associated

with exposure to consumer products is that the

dose is usually low, and the exposed population

tends to be very large. An adequate assessment

of the carcinogenic effect of a consumer product

might require a study of a million people,

on quantifying risk estimates from waterborne

carcinogens has focused on chloroform, since it

alone has consistently generated dose-response

data sufficient for extrapolating human risk. An

ad hoc study group of the EPA’s Hazardous Material’s Advisory Committee (158) estimated the

risk as follows:

The level of risk, estimated from consideration of the worst case [Miami, 311 ppb] and for

the expected cancer site for chloroform (the

liver), might be extrapolated to account for up

to 40% of the observed liver cancer incidence.

The results of a large NCI case-control study

which is examining possible relationships between water quality and bladder cancer are expected in 1981. Information was obtained in

that study on a wide range of demographic and

exposure factors and a data bank on water quality was created for more than 1,000 utilities

serving many of the people in the study. That

information will hopefully permit linking an individual’s risk factors with disease state. In addition, a case-control interview study to investigate relationships between drinking water and

colorectal cancer is being conducted (74).

whereas a study of only 1,000 workers might be

adequate in an occupational setting. Further,

while occupational exposure to a carcinogen is

frequently limited to a group of relatively

healthy workers, consumer exposure includes

subpopulation groups usually considered to be

“at high risk, ” such as infants, small children,

the elderly, and the infirm,

For most consumer products, available laboratory and human evidence is insufficient to

determine whether they pose a cancer risk. The

magnitude of the potential health hazard becomes apparent when one begins to examine

population exposure to different consumer

products. In 1973, U.S. production of aerosol

products was estimated at 2.9 billion units. A

recent Consumer Product Safety Commission

(CPSC) study indicated that manufacturers removed trichloroethylene (TCE), a widely used
Ch. 3—Factors Associated With Cancer ● 95

solvent in aerosol formulations, from consumer

aerosol product formulas after TCE was shown

to be carcinogenic in tests at NCI (117). The extent to which aerosol products containing TCE

has impacted on today’s cancer rates or how

many future cancers will result from past exposures is difficult to evaluate.

Attempts at quantifying potential adverse effects associated with consumer exposure to carcinogens are relatively new. In 1977, CPSC estimated that exposure of children to TRIStreated clothing could result in an excess risk of

cancer of up to 180 cases per million exposures.

Other examples of estimated consumer risk include up to 2,000 lifetime excess respiratory cancer deaths per million persons exposed to

MEDICAL DRUGS AND RADIATION

Medical practices have resulted in some devastating health crises, from the fatal puerperal

fevers of the 19th century maternity wards to

the millions who were exposed in utero to diethylstilbestrol (DES) and are now experiencing a

variety of adverse health effects, including at

least one type of cancer. Only drugs which have

been associated with cancer in humans will be

discussed in detail, but limited or inconclusive

evidence exists for many others, and still others

have not been investigated (see table 19).

The production of cancer, although always

an undesirable side effect, is not necessarily a

bar to the use of a drug if the risk of cancer

development is materially less than the medical

gains brought about by the treatment—e.g., by

the use of alkylating agents, immunosuppressive drugs and radiotherapy in the treatment of

cancer. The risks in some cases are known, as

with some cancer chemotherapy agents, but

more often are not suspected. Detection of disproportionate adverse effects through case reports and epidemiologic studies have caused the

abandonment of certain agents and treatments

for particular uses, for instance, inorganic

trivalent arsenic, chlornaphazine, DES during

pregnancy, and the radioactive agents thorium

and thorotrast.

asbestos-containing patching compounds; paint

stripper containing 52 percent benzene may present an excess risk of death from leukemia of up

to 50 per million people exposed; and people living in a residence insulated with urea-formaldehyde foam may beat an excess cancer risk of up

to 290 per million people exposed (117).

At this time it is impossible to assess the contribution of consumer products to the overall

cancer rate. Many industrial products have been

introduced so recently that even if they do prove

hazardous their effects would not yet be apparent. Doll and Peto (93) attribute “less than 1

percent” of all cancer deaths to such products,

but stress that there is too much ignorance for

complacency to be justified.

The causal link between in utero exposure to

DES, a synthetic estrogen, and subsequent development of a rare type of vaginal cancer in females (and possibly testicular cancer in males)

about 20 years later is a well-publicized example

of unsuspected risk. Between 4 million and 6

million Americans (mothers, daughters, sons)

were exposed to DES since about 1945 (258) in

efforts to prevent spontaneous abortions. As

later became evident, DES was an ineffective

therapy (90).

In this case, in spite of the long latency between in utero exposure and cancer development two or three decades later, the connection

was made between exposure and disease. The

facilitating factor in this case was the near nonexistence of the cancer type in the general population at the ages in which the disease was

seen. However, had the effect been a small excess of a common cancer, it is doubtful that the

association would have been uncovered. Since

the original association was uncovered, other

possible adverse effects have been suspected in

DES mothers, daughters and sons.

In cases of agents for which some risk is

known or suspected, the use of the agent is continued under controlled conditions, in the belief
96 Technologies for Determining Cancer Risks From the Environment

Table 19.—Drugs Associated with Cancer in Humans

Drugs established as human carcinogens

Drug Malignancy

Radioactive drugs: Organs where concentrated:

Phosphorus (P32) Acute leukemia, osteosarcoma,

Radium nasal sinus carcinoma, angiosarcoma

Mesothorium of the liver

Thorotrast

Chlornaphazine Bladder cancer

Arsenic Skin cancer

Methoxypsoralen Skin cancer

Alkylating agents: Acute nonlymphocytic leukemia

Melphalan, chlorambucil, other sites?

dihydroxybusulfan, busulphan, and others

Cyclophosphamide Bladder cancer

Immunosuppressive agents—Azothioprine Lymphoma, skin cancer, soft-tissue sarcoma

melanoma? liver and gallbladder?

lung adenocarcinoma?

Androgenic-anabolic steroids Hepatocellular carcinoma

Steroid contraceptives Endometrial carcinoma, liver tumors (benign)

breast cancer? cervical cancer? ovarian cancer?

choriocarcinoma? melanoma?

Estrogens:

DES (prenatal) Vaginal adenocarcinoma

Conjugated estrogens Endometrial carcinoma

breast cancer? ovarian cancer?

Phenacetin-containing drugs Renal pelvis carcinoma

bladder cancer?

Suspect drugs for which human evidence of carcinogenicity is either inconclusive or conflicting

Drug Malignancy

Chloramphenicol Leukemia

Iron Dextran Soft tissue sarcoma (site of injection)

Dilantin Lymphoma

Phenobarbital Brain tumors, liver cancer

Amphetamines Lymphoma

Reserpine Breast cancer

Progesterone (Depo-Provera) Cervical cancer

Phenylbutazone Leukemia

Crude tar ointment Skin cancer

Clofibrate Gastrointestinal and respiratory malignancies

Suspect drugs for which human studies have as yet not yielded evidence of carcinogenicity

Isoniazid

Metronidazole

Antimetabolites (Methotrexate, 5-Fluorouracil)

Suspect drugs as yet unevaluated in humans

Dapsone

Griseofulvin

Phenothiazines

Oxytetracycline

Chloroquin

SOURCE Hoover and Fraumenl (“73)
Ch, 3—Factors Associated With Cancer ● 97

that the benefit will prove to outweigh the

harm. Many of the known hazardous drugs are

used in the treatment of relatively uncommon

serious conditions and the sum of the cancers

caused by them can amount to no more than a

few score throughout the entire country each

year. However, some drugs, including oral contraceptives, and estrogens are or have been used

extensively. These and the medical use of ionizing radiation, also known to be carcinogenic,

are discussed below.

Oral Contraceptives

Oral contraceptives are taken by over 80 million healthy women the world over (366), spurring international concern about possible health

effects, Not surprisingly, the possibility of increased cancer risk after long-term use and a

long latent period has been the focus of major

epidemiologic efforts.

The evidence to date has clearly implicated

one type of sequential oral contraceptive (an

estrogen and a progestin taken separately during the first and second halves of the monthly

cycle), the use of which has been abandoned,

with some cases of endometrial cancer in young

women. Conversely, there is some evidence that

users of combination type oral contraceptives

(an estrogen and a progestin taken together in

the same pill) may be at slightly lower risk for

endometrial cancer (360).

In animal tests, both breast and liver cancers

have been induced by components of oral contraceptives. A small number of benign liver

tumors in humans have been associated with

certain types of oral contraceptives, and though

not cancers in the usual sense, they can cause

fatal internal hemorrhage. No controlled study

has yet evaluated the possible risk of malignant

liver tumors (173).

Studies of breast cancer in oral contraceptive

users have thus far yielded no clear-cut evidence

for either increased or decreased risk, except

perhaps some increase for women already at

high risk (see p. 99, Sexual Development,

Reproductive Patterns, and Sexual Practices for

a full discussion of risk factors). Cervical cancer

also has been studied extensively with no consistent findings.

There is some evidence to suggest that oral

contraceptives may reduce the risk of ovarian

cancer. The reduction may be related to lowered

levels of ovulatory activity, since high levels

have been associated with an increased risk of

ovarian cancer.

Because oral contraceptives have been part of

the American lifestyle for a relatively short

period, large numbers of users have not reached

old age, the period of greatest cancer risk. Until

such time, perhaps within the decade, the full effects cannot be known. Even then, because there

are many types of oral contraceptives, some of

which already have been shown to have different effects, and because formulations and

dosage levels have changed significantly over

time, risks identified for that first cohort may

not apply to today’s users. Overall, evaluating

the evidence available at this time, oral contraceptives do not appear to be a major cause of

cancer, but do require continued epidemiologic

attention.

Menopausal Estrogens

The use of “replacement estrogens” to relieve

menopausal symptoms became widespread in

the 1960’s. A sharp rise in the incidence of endometrial cancer followed through the mid1970’s in what has been termed “one of the

largest epidemics of iatrogenic disease , . . in

this country” (194). A cause-and-effect relationship was established through epidemiologic

studies, precipitating a decline in the use of these

agents. Shortly after the levels of use dropped,

incidence began to fall toward previous levels,

and the “epidemic” appears to be largely over.

Fortunately, these endometrial cancers have a

relatively good prognosis, and while morbidity

increased sharply, mortality attributable to estrogen therapy has not paralleled the incidence

trend. Estrogen therapy is still prescribed for

some women, generally for shorter periods of

time than previously. Used in this way, the risk

of endometrial cancer appears much lower,

though some cases may still occur, but the ben-
98 ● Technologies for Determinin g Cancer Risks From the Environment

efits of therapy are thought to outweigh the

residual risk.

Evidence has been accumulating that breast

cancer risk may be increased by menopausal estrogen therapy (173), particularl y among

women who develop benign breast disease while

taking estrogens (93). Unlike the case of endometrial cancer and estrogen therapy, where increased and decreased risk follow closely the

temporal pattern of usage, change in breast cancer risk appears to require many years to manifest itself.

Other associations between menopausal estrogens and cancer have been suggested. The

Boston Collaborative Drug Surveillance Program (30) reported increased gallbladder disease, which is a strong risk factor for cancer of

the gallbladder, among women who had estrogen therapy. Some studies have suggested an increased risk of ovarian cancer; others a decreased risk of some reproductive-site cancers

(173). Because of these uncertainties and the

long latent periods associated with many cancers, continued long-term followup is required

to determine if associations exist, and if so, the

magnitude of the risks.

Other Drugs of Known Carcinogenicity

Certain alkylating agents, a class of drugs

used primarily in the treatment of cancer, have

been convincingly associated with acute nonlymphocytic leukemia, known to have a relatively short latent period, and one agent in particular, cyclophosphamide, with bladder cancer. As survival improves for some treated cancers, increases may be seen in some other solid

tumors, which generally have longer latent

periods than leukemia.

Immunosuppressive agents, used widely in

transplant patients, greatly increase the risk of

lymphoma, and result in moderate increases in

tumors at several other sites. The sites which

show an increase are similar to those encountered with genetically determined immune deficiency syndromes and other conditions associated with immunodeficiency.

The initial report of a program designed to

screen large numbers of commonly used drugs

for carcinogenicity has recently appeared (133).

The followup period has been only 4 years, and

53 possible associations have been identified,

some with increased risk and some with decreased risk of cancer. Until a longer followup period

has elapsed, no conclusions of causality can be

reached. The importance of this type of surveillance mechanism lies in its long-term utility, in

identifying carcinogens and generating

hypotheses.

The Interagency Task Force on the Health Effects of Ionizing Radiation (182) estimated that

the collective dose of radiation received by the

U.S. population for medical purposes, mainly

diagnostic, amounts to about 18 million personrem per year. Using the linear model from BEIR

III (268), which produces a conservatively high

estimate, the risk of all types of cancer ranges

from 158 to 403 fatal cancers per million personrem. Applying these values to the total population yields an estimate of between 2,844 and

7,254 fatal cancers per year. Using the least conservative model, the lower risk estimate approached zero. However, some of the medically

associated radiation would have been received

by people with an expectation of life that was

too short for any significant chance of developing radiation-induced cancer (because of illness or age) and the total effect may be somewhat less.

Although well over half of the total population receives some medical radiation, the most

susceptible members of the population—unborn

fetuses—are of particular concern. Stewart,

et al. (333) in England and MacMahon (216) in

the United States first identified a risk to

children who had been exposed in utero, which

has been corroborated by numerous studies

since. There is also evidence that the risk of

childhood cancer is increased by X-rays of the

mother even before pregnancy (327), suggesting

that both germ cell (in this case, ovum) mutations as well as somatic (in the cells of the

developing child) may be important.

Pelvimetry, a radiographic examination used

to determine the pelvic dimensions of the

mother and the fetal headsize, is the major

source of ionizing radiation to fetuses. It has
Ch. 3–Factors Associated With Cancer ● 99

been estimated that in recent years, 6 percent

(about 200,000/yr) of all births have received

routine pelvimetry, and rates are much higher in

some places (46,198). The Food and Drug Administration (FDA) panel on X-ray pelvimetry,

in a statement adopted by the American College

of Radiology concluded that, “Pelvimetry is not

usually necessary or helpful in making the decision to perform a cesarean section. ” A similar

statement approved by the American College of

Obstetricians and Gynecologists states that: “Xray pelvimetry provides little additional information to physicians involved in the management of labor and delivery. ” Both groups

recommend that pelvimetry be limited to individual cases meeting specific criteria for

usefulness, and should not be used as a routine

examination (39). Although the actual numbers

of childhood cancers caused by medical radiation may be modest, the number could easily be

reduced by reductions in irradiation at least during and probably prior to pregnancy.

Unnecessary and unproductive radiation is

not limited to pelvimetry. The Bureau of Radiological Health (FDA) has addressed this issue by

beginning to prepare a series of documents addressing patient selection, conduct of examinations, and interpretation of results in radiographic procedures (38).

Doll and Peto (93) have estimated that about

1 percent of 1977 cancer deaths probably are attributable to medical practice. They go on to

say that the number of ways in which drugs

might in principle increase or decrease cancer incidence rates is almost limitless.

Higginson and Muir (163) attributed about 1

percent of all cancers in the Birmingham and

West Midland region of England (1968-72) to

iatrogenic causes. They note that the widespread use of estrogen therapy in the United

States might

U.S. women.

that about 4

cidence was

mones.

indicate a higher proportion for

Wynder and Gori (368) estimated

percent of 1976 U.S. cancer unassociated with exogenous horSEXUAL DEVELOPMENT, REPRODUCTIVE PATTERNS,

AND SEXUAL PRACTICES

Sexual development and reproductive patterns affect the development of a number of

cancers, affecting females to a greater degree

than males. The course of sexual development

itself may be heavily influenced by such factors

as diet and body composition (fat-to-lean ratio),

and reproductive patterns are often influenced

by economic and social conditions. Reproductive and dietary factors might well interact

multiplicatively in the production of these

cancers and there will be overlap between what

is preventable through diet and through reproductive factors. Doll and Peto (93) have estimated that about 7 percent (6 percent from

breast, ovarian, and endometrial cancers and 1

percent from cervical cancer) of all cancers

might be prevented by measures affecting the

mechanisms of reproduction and sexual factors.

Some evidence is consistent with cervical

cancer in women being associated with infectious agents and less certain evidence associating other genitourinary cancers with infection.

If this is true, some cancer-causing agents may

be transmitted as venereal diseases.

Cancers of the Breast, Ovary,

and Endometrium

The probability that environmental factors

contribute heavily to cancer of the breast, endometrium, and ovary is supported by international comparisons and studies of migrants. The

highest rates are found in white women in the

United States and Western Europe and the lowest among Asian women (see table 20) (184).

Lifestyle differences, particularly in diet and

reproductive patterns, are probably important

contributors to the rate differences. Migrant

studies in the United States have shown that the
100 ● Technologies for Determining Cancer Risks From the Environment

Table 20.–Selected International Age-Standardized incidence per 100,000

for Cancers of the Breast, Corpus Uteri, Cervix Uteri, Ovary, Prostate,

Testis and Penis

Females

Breast Corpus uteri Cervix uteri Ovary

Oxford, United Kingdom . . . . . . . . . . . . . 54.5 9.4 11.4 11.7

Alameda County, Calif., blacks. . . . . . . . 56.6 13.6 28.0 10.3

Alameda County, Calif., whites. . . . . . . . 76.1 33.3 12.3 13.5

Osaka, tJapan . . . . . . . . . . . . . . . . . . . . . . 12.1 0.9 16.2 2.8

Ibadan, Nigeria . . . . . . . . . . . . . . . . . . . . . 15.3 1.6 21.6 7.0

Males

Prostate Testis Penis

Oxford, United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2 2.6 0.7

Alameda County, Calif., blacks . . . . . . . . . . . . . . . . . . . . . . . 75.0 0.5

Alameda County, Calif., whites . . . . . . . . . . . . . . . . . . . . . . . 40.4 4.4 0.6

Osaka, Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7 0.7 0.5

Ibadan, Nigeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.0 0.1 0.2

SOURCE Data from International Agency for Research on Cancer (184)

initially lower rates for Mexican-Americans

(234) move toward the higher rates for whites in

the United States after a generation or two,

owing to shifts in lifestyle toward those of the

American population,

ACS (6) estimates that 110,000 women in the

United States will develop breast cancer in 1981,

and that 37,000 women will die from the disease. Breast, the leading site of cancer death in

women today, will account for approximately

19 percent of all female cancer deaths in 1981. A

host of studies has established a set of factors

that characterize women at high risk for breast

cancer (219). Age, geographic area of residence,

age at first childbirth, age at menarche (beginning of menstrual function), age at menopause

(cessation of menstrual function), history of

benign breast disease, and familial history of

breast cancer are the major predictors.

International comparisons of breast cancer

risk by age has provided the basis for hypotheses which have been examined in further

epidemiologic studies. In areas where incidence

is high (e.g., North America and Western Europe) the rate increases throughout life, often

with a break, where incidence decreases or at

least ceases to rise, at about 50 to 55 years of

age, after which it increases steeply once again.

In areas of low incidence (e.g., most areas of

Asia and Africa), rates increase through middle

age, decreasing after about age 50. Intermediate

patterns occur in areas of intermediate incidence

(e.g., Southern Europe and South America)

(219).

One basic hypothesis following from the

study of age-specific rates is that breast cancer is

best described as two diseases: one occurring

premenopausally and the other postmenopausally, each with different causes. De Waard

(79) presents some additional arguments from

epidemiologic research favoring this hypothesis.

Paffenbarger, Kampert, and Chang (289) have

recently added weight to the arguments against

the hypothesis, based on a large case-control

study of breast cancer, concluding that overall

the evidence supports a “common cause subject

to modifying influences” for all breast cancer.

The weight of evidence does not yet allow concluding whether breast cancer should be described as one disease or two.

Age at first childbirth is a strong predictor.

Giving birth to the first child after age 30, or

having no children at all place one at a greater

risk than giving birth to the first child before age

20 (238). A pregnancy must go to full term for

any protective effect. It is widely believed that

the first stimulus to lactation, whether or not

breast feeding is carried out, may be the factor

of consequence. Miller and Bulbrook (238),

reporting on a meeting of the Multi-Disciplinary
Ch. 3–Factors Associated With Cancer 101

Project on Breast Cancer of the International

Union against Cancer, speculate:

A population that achieved a 5-year reduction

in age at first delivery might achieve a 30-percent reduction in incidence of breast cancer.

An analysis of population-based cancer mortality rates (27) supports the correlation between nulliparity and higher rates. The data

suggest that, if the current pattern continues, the

decreasing fertility trends of the 1960’s and

1970’s may foretell increased breast cancer rates

for women in this decade.

Age at menarche has also been shown to have

some degree of predictive value in nearly all

breast cancer studies, with a lower age indicating a higher risk. Tulinius et al., (346) in their

study of Icelandic women, found a “slight influence” remaining after adjustment for parity

and age at first pregnancy. Henderson et al.

(162) found that women with menarche before

age 13 had 1-1/2 times the breast cancer risk of a

woman with later menarche.

Age at menarche, itself, maybe influenced by

environmental factors, notably nutrition. Population-based data reveal a steady decline in the

age at menarche for American women, thought

to be attributable to improved nutritional status

(238). The effect of this on future breast cancer

rates is uncertain. Early studies in rats correlated body size, more than age, with onset of

menarche (121). Similarly, observations in humans, including a recent look at menarche and

disturbances in the menstrual cycle of ballet

dancers (134), provide evidence that lean body

mass is related to later menarche. Later age at

menopause brings increased risk. Women with

natural menopause after age 55 have about

twice the risk of developing breast cancer as do

women with natural menopause before age 45

(219).

Breast cancer risk has a strong familial component that has not been entirely explained by

lifestyle similarities among relatives. First-degree (sisters, mothers and daughters) and second-degree (nieces and aunts) relatives of

women with breast cancer have two to three

times the risk of the general population. Relatives of women with bilateral breast cancer are

at higher risk, and are more likely to be diagnosed at an earlier age and to develop bilateral

disease than are relatives of women with unilateral disease (15).

Gray, Henderson, and Pike (144) looked at

the higher rate of breast cancer in U.S. white

women compared with U.S. black women.

They found that the relationship between black

and white rates is not constant. Below age 40,

black women have higher rates than whites,

while after age 45, black rates were 20 to 30 percent lower than those for whites. This can be

only partially explained by differences in age at

menarche, but a full explanation has not been

demonstrated.

Cancers of the endometrium and ovary share

at least two important risk factors with breast

cancer. They are all associated with high-fat

diets and women who have not borne children

are at an increased risk for all three types compared to women who have borne children. Occurrence of either breast or ovarian cancer increases the risk of a cancer developing at the

other site. Breast cancer also increases the risk

of future endometrial cancer (324). Ovarian

hormonal activity may be the influencing factor

in alI of these sites.

Cancer of the Cervix

There is a striking association between cancer

of the uterine cervix and the number of sexual

partners a woman has had. The death rate for

this cancer among nuns is much lower than it is

for the general population (129), suggesting the

involvement of a venereally transmitted agent.

A possible candidate is a virus (Herpes simplex

type II) which has been found in association

with both cervical cancer and other cervical cell

abnormalities (244). Some study results support

this hypothesis, but the data are considered only

suggestive at this point, and no conclusion of

causality can be drawn.

The number of deaths from cervical cancer

(ACS projects 7,200 in 1981) has decreased and

continues to decline, partially due to the more

widespread use of cervical screening (6). Based

on the assumption that the majority of cervical
102 ● Technologies for Determining Cancer Risks From the Environment

cancers are caused by infective processes, Doll

and Peto (93) estimate that prevention or treatment of infection might reduce total cancer mortality by 1 percent.

Cancers of Male Reproductive Organs

International comparison and a study of

Ugandan men has shown a correlation of higher

rates of penile cancer in areas where circumcision is not generally practiced and where penile

hygiene is poor (163),

Age-standardized incidence rates for prostate

cancer vary between about 3/100,000 in Japan

and 40/100,000 in U.S. whites, to a high of

about 75/100,000 for some U.S. blacks (184),

suggesting an environmental etiology. Feminella

NATURAL RADIATION

One would like to think that at least Mother

Nature would not place a carcinogenic burden

on the people of this planet. This unfortunately

is not the case. Several types of natural radiation cause concern regarding carcinogenicity,

the most important of which, ultraviolet radiation and ionizing radiation, were among the

first factors recognized as human carcinogens.

Ultraviolet Radiation

Ultraviolet radiation (or ultraviolet light) is

associated with some lip cancers, with a large

proportion of squamous-cell carcinomas and is

the principal cause of basal-cell carcinoma of

the face and neck in light-skinned people. The

evidence for the association includes prevalence

on sun-exposed areas, increased incidence in

lightly pigmented people, and increased incidence with greater insolation and greater time

outdoors. Basal-cell carcinomas account for

over 75 percent of all skin cancers, but appropriate treatment cures about 95 percent (159).

The squamous- and basal-cell carcinomas are

referred to as nonmelanoma skin cancer.

Approximately 400,000 cases occur annually–

as many cancers as occur at all other sites combined (66). Fortunately, most are not fatal.

and Lattimer (119) found an increase in cervical

carcinomas among wives of cases. A common,

perhaps viral, etiology is suggested; however it

is not substantiated by some population-based

rates, for instance, a lower rate of prostatic

cancer and a higher rate of cervical cancer occurs among Mexican-Americans as compared to

U.S. blacks (163).

Testicular cancer is highly associated with abnormalities of sexual development, particularly

cryptorchidism (failure of the testes to descend

into the scrotum) (208). Cancer occurs in 11 to

15 percent of undescended testes (s). The association may be direct or a third factor, perhaps

endocrinological,

both conditions.

may predispose individuals to

NCI conducted a nonmelanoma skin cancer

survey in eight locations in the United States

during the period 1977-78, as mandated by the

Clean Air Act Amendments of 1977. Men were

found to be at greater risk of cancer than were

women. The average age-adjusted incidence

rate for white males was 310/100,000 and for

white females 172/100,000 (250). An increase of

15 to 20 percent was reported in incidence as

compared to the rate estimated from the Third

National Cancer Survey (TNCS). This increase

may be due, in large part, to changes in clothing

styles and greater exposure to sunlight than was

customary years ago.

Ultraviolet radiation has also been associated

with the far more serious skin cancer, malignant

melanoma. However, the data are less convincing since the distribution of cancers on the body

does not directly correspond to the degree of exposure. In 1978, there were approximately 6,000

deaths from malignant melanoma in the United

States. ACS (6) estimates that there will be

14,300 new cases and 6,700 deaths from melanoma in 1981. Melanoma is the leading cause of

death from all diseases of the skin and is unquestionably increasing in frequency.

Incidence and mortality rates from skin cancer in different countries correlate fairly closely
Ch. 3—Factors Associated With Cancer ● 103

with the intensity of ultraviolet radiation. The

disease is most prevalent in people receiving

large amounts of sunlight, and it is a recognized

occupational hazard for individuals working

outdoors. The maps prepared by Mason, et al.

(223), which depict average age-adjusted cancer

mortality rates on a county-by-county basis,

convincingly demonstrate higher risk of skin

cancer in the Southeast United States. TNCS

found the annual incidence rate for nonmelanoma skin cancer to be 539/100,000 in the

Dallas-Fort Worth, Tex., area as compared to

174/100,000 in Iowa.

An individual’s risk of developing skin cancer

is strongly influenced by genetic makeup. A

higher risk exists for those with phenotypic

characteristics such as fair complexion, light eye

and hair color, and poor ability to tan. By contrast, skin cancer is very rare in deeply pigmented populations. In addition, several different types of chemicals can augment the carcinogenic properties of ultraviolet radiation, including some used as medications and in cosmetics.

As discussed in the Air Pollution section, the

use of chlorofluorocarbons has been restricted

in the United States because of the belief that

they may react in the stratosphere to reduce the

thickness of the ozone layer and cause an increase in ultraviolet radiation reaching the surface of the Earth. NAS (70) estimated that

global release of chlorofluorocarbons at 1977

rates could result in several hundred thousand

additional cases of nonmelanoma skin cancer

and several thousand melanomas in the next

century. (For additional information on the

possible carcinogenic impact from release of

chlorofluorocarbons, see Air Pollution. )

Higginson and Muir (166) estimated that 10

percent of male and female cancers in the Birmingham and West Midland region of England

could be attributed to sunlight. Doll and Peto

(93) attribute 90 percent of lip cancers (in conjunction with smoking), 50 percent or more of

melanomas, as well as 80 percent of other skin

cancers to ultraviolet radiation. This accounts

for between 1 and 2 percent of all cancer deaths

if these proportions are applied to 1978 U.S.

cancer deaths.

Ionizing Radiation

About half of the average U.S. exposure to

ionizing radiation comes from natural sources.

Of the remainder, most comes from diagnostic

medical exposures, and smaller amounts come

from medical therapy, occupational exposures,

and from radioactive pollutants. (Those exposures are discussed in Medical Drugs and Radiation, Occupation, and Air Pollution, respectively. ) Cosmic rays and the minute amounts of

radioactive isotopes that occur in our bodies

and in all natural materials are the major

sources of natural background radiation.

The quantitative dose-response relationship

between cancer and low-level ionizing radiation

has been the cause of much debate. Until 30

years ago, it was commonly assumed that ionizing radiation did not cause cancer unless the exposures were high enough to cause clinically

detectable damage to the irradiated tissue. This

assumption is now known to be false, although

the dose-response relationship at low levels is

still not known with certainty.

Organs and tissues differ in their susceptibility to carcinogenic effects induced by radiation.

Leukemia was the first form of cancer associated

with exposure to ionizing radiation, but we now

know that cancer may be induced by radiation

in many tissues of the human body and that the

risk of inducing solid tumors exceeds that of leukemia (268). The major cancer sites affected are

the breast in women and the thyroid, lung, and

digestive organs in both sexes. Solid tumors

have a longer latency period (10 to more than 30

years) than the few years before the excess risk

for leukemia manifests itself. The total cancer

risk from radiation is greater for women than

men, principally because of the contribution of

breast cancer.

More information is available on the doseresponse relationship between radiation and

cancer than any other, but there is still much

controversy over the appropriate extrapolation

model to use for estimating the cancer risk from

ionizing radiation. In July 1980, NAS officially

released BEIR III (268). The estimates for the

risks from ionizing radiation used by BEIR 111

were derived principally from human experi-
104 ● Technologies for Determining Cancer Risks From the Enviromnent

ences with much higher doses than most people

receive. The most important of these are data

from populations exposed to atomic blasts in

Hiroshima and Nagasaki, patients exposed to

therapeutic radiation, and various occupational

groups such as uranium miners and radium

watch dial painters. Disagreement persists in the

field of radiation carcinogenesis over the appropriateness of these high-exposure populations

for estimating low-level risks.

The development and release of the BEIR 111

report illustrates the diverging and changing

opinions concerning the appropriate methodology for extrapolating from the measured effects

of high doses of ionizing radiation to the most

probable effects of low doses. A draft of the

BEIR 111 report was released for public comment

in May 1979 but was retracted when it was

learned that a majority of the committee supported a model different from the one presented.

Some members of the committee felt that for

low doses, a linear model overestimated the risk

and a pure quadratic model, which estimates a

lower risk, could be used as a lower bound.

However, others felt that the linear model was

more accurate. Because of this disagreement, a

consensus panel was assembled and it adopted

the linear-quadratic model: the pure quadratic

model produces the lowest estimate, the linear

the highest, and the linear-quadratic estimates

an intermediate risk. Depending on which model is used, estimates of mortality from all forms

of cancer will differ by about one order of magnitude.

The committee also could not agree on whether the cancer risk from radiation would have an

additive or multiplicative effect on the general

cancer rate. Throughout the report, excess risk

is given as both an absolute (additive) and as a

relative risk. The relative approach assumes

that the excess risk increases gradually and continuously, proportional to the spontaneous risk,

which increases with age for nearly all cancers.

The absolute approach assumes a constant number of additional cancers throughout life.

The BEIR III report (268) makes various attempts at estimating cancer risk from different

types of exposure but does not quantify the risk

from low-dose radiation:

. . . the degree of risk is so low that it cannot be

observed directly and there is great uncertainty

as to the dose-response function most appropriate for extrapolating in the low-dose region.

It further states:

It is by no means clear whether dose rates of

gamma or x radiation of about 100 mrads/yr are

in any way detrimental to exposed people . . .

For the purpose of this assessment, the risks

derived for continuous lifetime exposure to 1

rad/yr of low-dose (gamma or X-ray) radiation

is the most relevant, though it is an order of

magnitude higher than average natural background radiation. Table 21 displays both absolute and relative risk estimates generated by

BEIR III.

The BEIR III report estimated that the average

whole body dose of natural background radiation in the United States is approximately 100

mrem/yr. The dose of radiation received varies

with altitude and geographical location. Using a

figure of 220 million Americans, one can estimate that the population as a whole would be

exposed to 22 million person-rem of background radiation.3 Although BEIR III did not attempt to estimate the risk of cancer induced by

low-dose radiation, it would not be incorrect to

compute an upper limit of risk from the linear

model since this is the only model which

assumes that dose and effect are proportional.

Using the range of risk estimates, 158-403 excess cancer deaths per million persons per rad,

yields estimates of 3,476 and 8,866 cancer

deaths per year attributable to background

radiation. These figures represent between 0.9

and 2.2 percent of all cancer deaths, and are

comparable with 3-percent estimates by Doll

3

1n 1972, EPA estimated that the average dose of natural background radiation for a person living in the United States is 130

mrem. Based on this estimate, the Interagency Task Force on the

Health Effects of Ionizing Radiation estimated that the U.S. population is exposed to 20 million person-rem, but this is in error because dividing 20 million person-rem by 130 mrem produces a

quotient of 154 million people. The population is nearer 22o

million.
Ch. 3–Factors Associated With Cancer ● 105

and Peto (93) and Jablon and Bailar (191). The zero, in keeping with risks derived from other

lower estimate can be considered to approach models, including the quadratic model.

Table 21 .—Estimates of Excess Cancer Mortality From Continuous Exposure

to 1 Rad/Year of Low-Level (background-type) Radiation by Three Dose-Response

Models and Two Risk Projection Models

Estimates of excess annual cancer mortality from continuous exposure to 1 rad/year

of low-level (background-type) radiation (excess deaths/million exposed and percentage of

normal expectation of cancer deaths)

Risk projection model

Dose-response model Absolute Relative

Normal expectation of

cancer deaths 167,300 167,300

Linear quadratic Excess deaths: number 4,751 12,920

Percent of normal 2.8 7.7

Linear Excess deaths: number 11,250 30,520

Percent of normal 6.7 18.2

Quadratic Excess deaths a a

aNot calculated because estimates very close to zero

Estimates of excess lifetime cancer mortality from continuous exposure to 1 rad/year

of low-level (background-type) radiation (excess deaths/million exposed)

Dose-response mode l

Risk projection model

Absolute Relative

Linear quadratic 67 182

Linear 158 403

Quadratic — —

SOURCE: Tables adapted from (270)

INFECTION

Infection, particularly viral infection, has

long been thought to be a cause of cancer. This

idea is partially based on the observation that

neoplasms appear in many animal species following viral infections, and specific animal

tumor viruses have been convincingly identified. However, epidemiologic evidence indicates

that cancer is not a contagious disease. People

who come into close contact with cancer patients, such as nurses, doctors, and spouses of

patients, are at no higher risk of developing the

disease than others. Reports are occasionally

published of the occurrence of an unusually

large number of cases of rare cancers, but such

clusters can be expected to occur periodically by

chance. It is more plausible that certain viruses

exist which are important in the development of

some types of cancer, but that they are widespread in the community. It is probably not the

virus itself, but a variety of other factors which

determine whether the virus will lead to the development of the disease. These may include

genetic and hormonal factors, chemical carcinogens, and defective immune mechanisms, which

appear to exert an effect in only a small proportion of those exposed.

The strongest evidence implicating a viral infection in human cancer causation concerns

Epstein-Barr virus (EBV) and hepatitis B virus,

believed responsible for several cancer types

which are relatively rare in the United States.

Epstein-Barr is a herpesvirus which is strongly

associated with Burkitt’s lymphoma and naso-
106 ● Technologies for Determining Cancer Risks From the Environment

pharyngeal carcinoma (93,304). EBV occurs

ubiquitously and is known to be the specific

cause of infectious mononucleosis. It is postulated that the viral DNA integrates into the genetic material of a human stem cell and that cell

becomes the parent of a malignant clone. Epidemiologic data and the detection of EpsteinBarr viral DNA in lymphoma cells supports the

association between the virus and these two

cancers. The association with nasopharyngeal

carcinoma, found in the Far East, is not so

strong as with Burkitt’s Iymphoma, which occurs mainly in children in central Africa and

New Guinea. Nasopharyngeal carcinoma is believed to involve a stronger genetic component,

since Chinese migrating to the United States

have a much higher incidence of the disease than

U.S. whites and blacks, but the rate is lower

than among Chinese remaining in the Far East

(128). The unusual geographical distribution

suggests that the virus may act as a cocarcinogen and that additional factors, such as

immunosuppression as a result of malaria, may

be involved.

Hepatitis B virus is associated with chronic

liver infection which often advances to hepatocarcinoma. A greater prevalence of active

hepatitis B infection has been demonstrated in

patients with primary hepatocellular carcinoma

as compared with matched controls and the general population (304). The virus is believed to be

the initiating agent, but promoting agents such

as aflatoxin may be important cofactors (304).

Two other herpesviruses are suspected of being

associated with cancer: herpes simplex virus

type 2 with cervical cancer, and less closely,

cytomegalovirus with prostatic and cervical

cancers.

The vast majority of human cancers are not

characterized by the presence of viral DNA in

the genetic material of cells. This may, of

course, be because the methods currently used

to detect the presence of a virus are not sufficiently sensitive, or it may be that viruses are

not often associated with cancer.

Doll and Peto (93) suggest that viral infection

may eventually be shown to be an essential factor in the production of some cancers:

●

●

●

●

If

cancer of the uterine cervix—women with

multiple partners are at high risk (see Sexual Development, Reproductive Patterns,

and Sexual Practices);

cancer of the penis—wives of penis cancer

patients are at high risk for cancer of the

uterine cervix;

acute lymphatic leukemia in children—disease may recur in donor cells after a marrow transplant; and

reticulosarcoma —occasional appearance

shortly after receiving doses of immunosuppressive drugs.

all of the above cancers depended on viral

infection, the proportion of cancers attributable

to infection would be about 4 percent (93). The

proportion may be considerably larger if, like

diet, infectious agents act by indirect means to

contribute to the production of cancers. Viruses

may promote the development of cancer by

causing tissue death, thereby stimulating the

division of stem cells and sensitizing them to the

action of chemical carcinogens. It is possible for

instance, that this is the mechanism whereby

hepatitis B virus is associated with the development of liver cancer.

Infection with bacteria or parasites may also

contribute to the production of cancer. The Diet

section discusses the possible role of intestinal

bacteria in producing or destroying carcinogenic metabolizes in the large bowel and of

salivary duct bacteria in converting nitrates into

nitrites and hence facilitating the formation of

N-nitroso compounds in vivo. Bacterial infection associated with the development of chronic

bronchitis has been thought to increase the risk

of lung cancer in cigarette smokers (93), possibly by impairing the efficiency of the mechanism for clearing the bronchi and hence permitting more prolonged contact between inspired

carcinogens and the bronchial stem cells. A

similar role for infection may also explain the

association between ulcerative colitis and colorectal cancer, and that between schistosomiasis, a parasitic infection of the bladder common in parts of Africa, and the development of

bladder cancer.
Ch. 3–Factors Associated With Ca/leer ● 107

The examples cited are unlikely to be the only

ways in which infection affects the risk of developing cancer; but even if they were, the range

of estimates for its contribution to the overall

cancer rate would be large. Rapp (304) speculated that if herpesviruses are eventually shown

to be involved in all cancers of the male and

female genitourinary systems, then those with

active venereal disease would have a 1 per

70-100 risk of developing the disease:

This estimate is based on the number of new

genitourinary cancer cases per year in the United

States (100,000 for females and 70,000 for males)

in a population containing about 14 million active cases . . . of venereal disease due to herpesviruses.

If one applies this reasoning to 1978 U.S. cancer

deaths, approximately 15 percent of all cancer

mortality would be associated with infection.

This estimate is extremely tentative—there is

much more certainty around the association

with cervical cancer than other genital sites.

Doll and Peto (93) suggested a figure about 10

percent as a very uncertain best estimate, within

a very wide range of acceptable estimates, of the

proportion of cancer deaths attributable to infection, distributed as follows:

. . . 5% perhaps attributable to the action of

viruses and a token figure of 5% to allow for the

possible role of other infective agents in determining the conditions under which cancer is produced in vivo. The likely role of infectious

agents in the etiology of cancer of the uterine

cervix provides a lower limit of at least 1%, but

we can at present make no useful guess at the upper limit.

OTHER OR UNKNOWN ASSOCIATIONS

Two basic classes of “other” associations will

be considered:

1. Associations with cancers which as yet remain unidentified, but which, when elucidated, will most likely fall into categories

that have been discussed in this chapter.

2. Associations of agents or exposures with

cancers of the future. These may have

been introduced recently, but have not yet

produced cancers, or may be introduced

in the future.

Causes of Cancers Occurring Today

The agents associated with and/or responsible for many of today’s cancers have not been

identified. For example, although cancers of the

breast, colon, rectum, and stomach are associated in some way with dietary factors, a causal

relationship has not been found for cancers at

those sites. Additionally the incidence of some

cancers, myelomatosis and non-Hodgkins lymphoma, for example, appear to be increasing

but no evidence associates those cancers with

even a broad category of factors.

The search for environmental factors associated with cancer will undoubtedly continue.

Observed differences in rates between populations, within countries, and through international comparisons will result in advancing

new hypotheses and promoting further studies.

Some suggested associations that were not

discussed above are likely to be further investigated, but currently few data exist about

them. Biological factors, like immunologic control, may normally limit the onset of disease,

and a breakdown of this mechanism which may

be brought on by an environmental agent, could

increase the propensity for cancer development.

Similarly, psychological factors such as stress

may create an internal milieu suitable for tumor

growth. There is some animal evidence to support this hypothesis but it is limited. Studies of

patients in mental hospitals are not supportive

of an increased risk (93). Psychological stress

does have a recognized role in causing people to

smoke, drink, overeat, and take part in other

harmful activities which may directly or indirectly increase their risk of cancer.
108 ● Technologies for Determining Cancer Risks From the Environment

New Cancer Associations

Hazards exist today which may not have

caused any cancers, but which may do so in the

future. A timely example is hazardous wastes

that have been improperly disposed of in areas

commonly termed “dumps. ” EPA has estimated

that there are more than 50,000 improperly

operated dump sites containing hazardous

waste that are not being properly operated. Of

these, they estimate that 30,000 pose a significant health risk. The carcinogenic potential of

the myriad chemicals in these dumps is unknown at present. (An OTA assessment about

nonnuclear industrial wastes, which will look at

health risks, among other things, is to be completed in late 1982. )

Hundreds of new chemicals are introduced

into commerce each year. Some of these may

present cancer risks. Exposures may be through

many routes—pollution, occupation, consumer

products, foods, or others.

Table 22.—Estimates of the Percentage of Total Cancer Associated with Various Factors

Time period

to which

Factor Estimate estimate applies Author

Tobacco

30% U.S. mortality, males and females combined

25-35°/0 U.S. male mortality population

5-100/o U.S. female mortality

24-38% various populations

430/0 US. male incidence

18°/0 U.S. female incidence

51% . U.S. male mortality

260/o U.S. female mortality

300/o male cancers, Englanda

7% female cancers, Englanda

1977

1960-72

1960-72

—

1980

1980

1980

1980

1968-72

1968-72

28% U.S. male incidenc e

%

80/0 U.S. female incidence

Alcohol

4-50/. of mortality, males and

140/0 U.S. male mortality

12% U.S. female mortalitv

1976

1976

females combined 1978

1974

1974

3% U.S. mortality, males and females combined

(approximately 4.6% for males and 1°/0 for females)

4% U.S. male incidenceb

1% U.S. female incidenceb

50/0 male cancers, Englanda (tobacco/alcohol)

3% female cancers Englanda (tobacco/alcohol)

Diet

4094. U.S. male incidence

600/o U.S. female incidence

350/o U.S. mortality, males and females combined

Occupation

4% U.S. male incidence

2% U.S. female incidence

6% male cancers, Englanda

2% female cancers, Englanda

<15% U.S. male cancers

< 5% U.S. female cancers

23-38°/0 U.S. incidence, males and females combined

6.8% U.S. male mortality

1.20/0 U.S. female mortality

1977

1976

1976

1968-72

1968-72

1976

1976

1977

1976

1976

1968-72

1968-72

Not specified

Not specified

Near term and

future

1977

1977

Doll and Peto (93)

Hammond and Seidman (155)

Hammond and Seidman (155)

Enstrom (100)

U.S. Surgeon General (287)

U.S. Surgeon General (287)

U.S. Surgeon General (287)

U.S. Surgeon General (287)

Higginson and Muir (166)

Higginson and Muir (166)

Wynder and Gori (368)

Wynder and Gori (368)

OTA based on Schottenfeld

(323)

Rothman (313)

Rothman (313)

Doll and Peto (193)

Wynder and Gori (368)

Wynder and Gori (368)

Higginson and Muir (166)

Higginson and Muir (166)

Wynder and Gori (368)

Wynder and Gori (368)

Doll and Peto (93)

Wynder and Gori (368)

Wynder and Gori (368)

Higginson and Muir (166)

Higginson and Muir (166)

Cole (62)

Cole (62)

HEW (82)

Doll and Peto (93)

Doll and Peto (93)
Ch. 3–Factors Associated With Cancer ● 109

Table 22.–Estimates of the Percentage of Total Cancer Associated with Various Factors (Continued)

Time period

to which

Factor Estimate estimate applies Author

Asbestos

13-18°/0 U.S. cancers

30/0 (1 .4-4.4°/0) U.S. cancers

Air pollution

20/0 U.S. mortality

Consumer products

< 1% U.S. mortality, males and females combined

Infection

5%?-10%?? U.S. cancers

150/0 U.S. mortality

Lifestyle

30% male cancers, Englanda

630/o female cancers, England a

Radiation, natural and medical:

Ultraviolet

10°/0 male cancers, Englanda

10°/0 female cancers, Englanda

Unspecified radiation

1% male cancers, Englanda

1% female cancers, Englanda

Ultraviolet and X-ray

8°/0 U.S. male incidence

8°/0 U.S. female incidence

Natural ionizing

O-(0.9-2.2°/0) U.S. mortality

30/0 U.S. mortality

30/0 U.S. mortality

Medical drugs and radiation

10/0 U.S. mortality, males and females combined

10/0 male and female cancers combined, Englanda

4°/0 U.S. incidence, males and females combined (refers only

to exogenous hormones)

Sexual development, reproductive patterns and sexual practices

7°/0 U.S. mortality, males and females combined

Other or unknown

?%

15°/0 male cancers, Englanda

11% female cancers. Englanda

Near term and

future

Now or likely in

near future

Future

1977

Present and

future

1978

1968-72

1968-72

1968-72

1968-72

1968-72

1968-72

1976

1976

1978

1978

1978

1977

1968-72

1976

1977

Present and

future

1968-72

1968-72

HEW (82)

Hogan and Heel (171)

Doll and Peto (93)

Doll and Peto (93)

Doll and Peto (93)

Rapp (304)

Higginson and Muir (166)

Higginson and Muir (166)

Higginson and Muir (166)

Higginson and Muir (166)

Higginson and Muir (166)

Higginson and Muir (166)

Wynder and Gori (368)

Wynder and Gori (368)

OTA based on BEIR Ill (268)

Doll and Peto (93)

JabIon and Bailar (191)

Doll and Peto (93)

Higginson and Muir (166)

Wynder and Gori (368)

Doll and Peto (93)

Doll and Peto (93)

Higginson and Muir (166)

Higginson and Muir (166) , - --

aBlrmlngham and West Midland Region.

bEstimated from graphic presentation.

SOURCE: Office of Technology Assessment.
4

Methods for Detecting and

Identifying Carcinogens
Contents

Page

Methods . . . . . . . . .......................113

Analysis of Molecular Structure and Other

Physical Constants, . ..................114

Short-Term Tests . .......................115

The Ames Test. . . ......................116

Other Short-TermTests. . ................120

Use of Short-TermTestResults andPolicy

Statements About the Tests . ......,.....121

Bioassays . . . . . . . . . . . . . . . . . . . . . . . . .. ....122

Standard Protocols for Bioassays. . .........123

Objections to the Usefulness of Bioassays ....124

Expert Review of Bioassay Results . .........127

Policy Considerations About Bioassays. ... ..l28

How Many Chemicals Are Carcinogens in

Animal Tests? . ......................129

Selection of Chemicals forTesting in Bioassays

and Short-Term Tests . . . . . . . . . . . . . . . ..131

The Interagency Testing Committee . .......131

National Toxicology Program . ............133

The National Center for Toxicological

Research . ..........................13 4

Chemical Industry Institute of Toxicology. ...l35

Tier Testing. . . . . . . . . . . . . . . . . . . ... .;. ....135

Epidemiology . ........................136

Descriptive Epidemiology . ...............137

Observational Epidemiology. . ............137

Causal Associations. . ...................138

Policy Considerations About Epidemiology. ..l38

Carcinogens for Which There is Human

Evidence . ..........................14 6

Annual Report on Carcinogens . ...........140

Sources of Epidemiologically Useful Data ... ...l42

Health Status Information. . ..............142

Exposure Data. . . . . . . . . . . . . . . . . ... ... ..145

Chemical Information Systems . ...........146

Collection and Coordination of Exposure

and Health Data. . . . . . . . . . . . . . . . . . . . . .149

Government Records and Record Linkage. ...l5l

Summary . .............................15 2

LIST OF TABLES

Table No. Page

23. General Classification of Tests Available

24.

25.

26.

27.

28.

29.

30.

31.

To Determine Properties Related to

Carcinogenicity. . . . ...................114

Results Obtained in Two Validation Studies

of the Ames Test WhenKnown

Carcinogens and Noncarcinogens Were

Tested . . . . . . . . . . ....................118

Expected Results of Examining Two

Collections of Chemicals for Mutagenicity

Using a Short-Term Test That is 90-Percent

Sensitive and 90-Percent Specific: One

Collection of Chemicals Contains 1 Percent

Carcinogens; the Other Contains 10Percent .119

Distribution and Number of Animals in a

Typical Bioassay Study of Carcinogens. ....124

Guidelines for Bioassay in SmalI Rodents ...125

Some Organizations That Have Considered

and Endorsed Animal Tests as Predictors of

Human Risk From Chemical Carcinogens ...l29

Advantages and Disadvantages of CaseControl and Cohort Studies .. ... ... :. ...139

Chemicals and Industrial Processes

Evaluated for Human Carcinogenicity by

the International Agency for Research

on Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . .141

EPA’s Recommended Base Set of Data To

Be Included in Premanufacturing Notices ...148

LIST OF FIGURES

Figure No. Page

19. Molecular Structures of Two Closely

Related Chemicals: One a Carcinogen and

One a Noncarcinogen . .................115

20. 1nterrelationships of Major Testing

Activities of NTP . ....................136
4.

Methods for Detecting and

Identifying Carcinogens

Beginning with this chapter, the focus of this

report shifts from all causes of cancer to only

chemicals. This shift does not represent a decision that chemicals, in the workplace or in the

general environment, are more important in

cancer causation than dietary elements, personal habits, radiation, or certain aspects of

human biology. However, it does reflect the major legislative and regulatory emphasis recently

placed on chemicals, and the greater ease with

METHODS

There are four major methods for detecting

and identifying carcinogens:

1.

2.

3.

4.

molecular structure analysis,

short-term tests,

long-term chronic bioassays in laboratory

animals (termed “bioassays” or “animal

tests” hereafter), and

epidemiology.

The first two methods produce information

about potential carcinogenicity; the third provides direct evidence of carcinogenicity in

animals; the fourth produces direct evidence

about cancer in man. These categories are briefly described in table 23.

Probably no statement made in the last column of table 23 is free from dispute. Results

may be, and frequently are, challenged for several reasons: because the test was incorrectly designed or executed (all methods); because the

method does not directly measure carcinogenicity (methods 1 and 2); because the test is too

sensitive and produces false positives (methods

2 and 3); because the test is too insensitive and

produces false negatives (method 4); and because the test does not measure human experience (all methods but 4), etc.

which chemical carcinogens can be detected by

present-day methods.

Different methods are available, employing

different techniques, using different test organisms, and producing different types of information about carcinogenicity. This chapter

discusses a variety of those methods, their

strengths and weaknesses, some results from

each, and the tools they require.

Knowledge about tests and about the validity

of test results increases as the tests are more

often used, more discussed, and more refined.

The state of scientific knowledge plays an important role in decisions to test or not to test a

chemical, decisions about which tests are appropriate, and decisions about interpretation of the

test results. As will be discussed, “policy statemerits, ” sometimes issued as guidelines or standards, detail the methods that an organization

will use in making decisions. A certain tension is

apparent in all the policies. Tests cost money

and take time; bigger and better tests cost more

and take more time; compromises are necessary

in the design of each test so that a reasonable

number of chemicals can be tested.

An equally important issue is the amount of

information necessary to decide that a chemical

is or is not a carcinogen that requires some control action. The fact that some regulations are

based on nonhuman test systems shows that

proof that a chemical is a human carcinogen is

not demanded. This illustrates that prevention

of cancer is seen as so important that it is appropriate to make decisions to restrict exposures

before human damage is observed.

113
114 ● Technologies for Determining Cancer Risks From the Environment

Table 23.—General Classification of Tests Available To Determine Properties Related to Carcinogenicity

Time Conclusion, if result

Method System required Basis for test Result is positive

Molecular “Paper chem- Days

structure istry”

analysis

Basic labor- Weeks

atory tests

Short-term Bacteria, yeast, Generally

tests cultured cells, few weeks

intact animals (range 1 day

to 8 months)

Bioassay Intact animals

(rats, mice) 2 to 5 years

Epidemiology Humans Months to

lifetimes

Chemicals with

like structures

interact similarly

with DNA

Chemical interaction with DNA

can be measured

in biological

systems

Chemicals that

cause tumors in

animals may

cause tumors in

humans

Chemicals that

cause cancer

can be detected

in studies of

human

populations

Structure resembles

(positive) or does not

resemble (negative)

structure of known

carcinogen

Chemical causes

(positive) or does not

cause (negative) a response known to be

caused by carcinogens

Chemical causes (positive) or does not cause

(negative) increased incidence of tumors

Chemical is associated

(positive) or is not associated (negative) with

an increased incidence

of cancer

Chemical may be

hazardous. That determination requires

further testing.

Chemical is a potential carcinogen.

Chemical is recognized

as a carcinogen in that

species and as a potential human carcinogen.

Chemical is recognized

as a human carcinogen.

SOURCE Office of Technology Assessment

ANALYSIS OF MOLECULAR STRUCTURE AND

OTHER PHYSICAL CONSTANTS

Some information about the likelihood of a

chemical being a carcinogen maybe obtained by

comparing its structure and chemical and physical characteristics with those of known carcinogens and noncarcinogens. This first stage in an

orderly determination of whether or not a chemical is a carcinogen requires the gathering of all

available information about it. The information

can be obtained from sources as diverse as results from testing a chemical in animals to anecdotal stories about human disease, but the most

readily available information is often about the

molecular structure and physical and chemical

properties of the suspect chemical.

Certain molecular structures have been associated with carcinogenicity, and structural similarity is used in making decisions about which

agents are more or less suspect. For instance, 8

of the first 14 carcinogens regulated by the

Occupational Safety and Health Administration

(OSHA) are aromatic amines. The Environmental Protection Agency (EPA) relies heavily

on structural analysis in determining whether or

not “new” chemicals, described in premanufacturing notices, may present an unreasonable

risk to health or the environment. Chemical and

physical properties which are useful in evaluating a chemical’s carcinogenic potential include

volubility, stability, sensitivity to pH, and

chemical reactivity. Often this type of information is generated by the manufacturer of the

chemical.

A number of proposals have been made that

chemicals be divided up into classes depending

on their structural similarities and that testing

be done on a number of members in each class.

Unfortunately, carcinogens are known in several chemical classes, and “ . . . the dozen or

more known classes of these agents [carcinogens] share no common structural features”

(239). Furthermore, even within classes, closely

related chemicals may differ with respect to carcinogenicity—e.g., 2-acetylaminofluorene (2-

AAF) is a well-documented carcinogen; its
Ch. 4—Metkods for Detecting and ldentifying Carcinogens ● 115

chemical relative, 4-acetylaminofluorene (4-

AAF), is not a carcinogen (see figure 19).

Figure 19.— Molecular Structures of Two Closely

Related Chemicals: One a Carcinogen and

One a Noncarcinogen

2-acetylamlnofluorene, a known carcinogen

4-acetylaminofluorene, a noncarcinogen

SOURCE. Off Ice of Technology Assessment

EPA recently based a regulatory decision on

molecular structural analysis. Under section 5(e)

of the Toxic Substances Control Act (TSCA),

EPA prohibited the entry of six new chemical

substances into the marketplace unless the

manufacturer provided additional information

about toxicity. A National Cancer Institute

(NCI) bioassay had shown a related chemical to

be carcinogenic, and based on that result, EPA

decided that more information was needed before manufacture could begin (88). The manufacturer decided not to proceed with the testing

and did not market the chemicals.

Short-term tests are so named because of the

relatively short time needed to conduct the experiments. Some studies involving micro-organisms require less than 1 day to complete (87),

most require a few days to a few weeks, and the

longest, using mice, requires 8 to 9 months

(172), These times may be compared to the

more than 3 years required to complete a bioassay and the months to years required to complete epidemiologic studies.

A number of reasons account for the growing

interest in using short-term tests to predict a

chemical’s carcinogenic potential:

● shorter time period required for the tests;

● low cost ($100 to a few thousand dollars for

each test compared to $400,000 to $1 million for a bioassay);

● evidence that the majority of chemical carcinogens are mutagens and that many mutagens are carcinogens;

● growing opinion that short-term tests

can predict which chemicals may be carcinogens.

The third point is important because many

short-term tests determine whether or not a

chemical causes mutations (mutagenicity) rather

than if it causes cancer (carcinogenicity). The

postulated relationship between mutagenicity

and carcinogenicity stems from biological properties common to all living organisms. The

genetic information in both germ cells (egg and

sperm) and somatic cells (nongerm or “body

cells”) is composed of deoxyribonucleic acid

(DNA), and agents that cause mutations in germ

cells are also expected to cause mutations in

somatic cells. A germ cell mutation may prevent
116 ● Technologies for Determining Cancer Risks From the Environment

the formation of viable offspring, cause a genetic malformation, or produce subtle defects in

the progeny, such as minimal depression in intelligence or increased susceptibility to disease.

The consequences of somatic cell mutations

are quite different from those in germ cells.

Somatic cells do not contribute genetic information to succeeding generations, but as each somatic cell grows and divides, copies of its DNA

are passed on to its two “daughter” cells. Some

somatic cell mutations result in uncontrolled

cellular growth: The normal tightly controlled

growth pattern of the somatic cell is broken

down, the cell grows and divides more quickly

than it should, progeny cells exhibit the same

uncontrolled growth, and cancer results.

The hypothesis that assigns genetic changes in

somatic cells a role in cancer initiation is referred to as “the somatic mutation theory of

cancer.” Cairns (42) discusses the origin and

development of this theory, which provides intellectual support for associating mutagenicity

and related changes measured in short-term

tests with potential carcinogenicity.

The short-term tests that depend on mutagenicity can detect only materials that interact

with DNA. Some cancers may be caused by

other, “epigenetic,” pathways that may not involve alterations in genetic information (317).

Short-term tests cannot detect such activities.

Additionally, short-term tests do not detect promoters that do not interact with DNA. The generally good correlation between mutagenic and

carcinogenic activity as well as the bulk of

results from basic cancer biological research

support the notion that carcinogens generally

interact with DNA.

The Ames Test

The most widely used and best-studied shortterm test, the “Ames test, ” is named for its

developer, Bruce Ames, a molecular biologist.

The test measures the capacity of a chemical to

cause mutations in the bacterium Salmonella

typhimurium, a favorite tool for laboratory investigations since the 1940’s. Salmonella’s

genetics and biochemistry are well understood:

it is quickly and easily grown; it presents few

manipulative problems in the laboratory, and

test results are easily interpretable and reproducible between laboratories.

Basically, the Ames test involves mixing the

chemical under test with a bacterial culture and

then manipulating the culture so that only mutated bacteria will grow. The number of mutated bacteria is a measure of the potency of the

tested material as a mutagen.

It is well known that some chemicals must be

altered before they interact with DNA and that

in humans and other mammals these changes

are often accomplished by enzymes in the liver.

The addition of liver extracts to the Ames test

system and to other short-term tests provides

a mechanism for these metabolic activation

changes to be accomplished. Generally, extracts

are prepared from rats, hamsters, or other laboratory animals. The source of the extracts and

the amount used in the tests affect results, and

careful experiments report these specifics so that

others can replicate the tests. Some chemicals

are “activated” by bacteria normally present in

the intestine rather than by the liver. The

addition of extracts of such bacteria to Ames

test mixtures has been shown to activate some

chemicals to mutagenic forms (338).

As of early 1979, more than 2,600 Ames test

results had been published (172). The interested

reader is referred to Hollstein et al. (172) and

Devoret (87) for more detailed descriptions of

the tests, to Ames (11) for a description of the

problems of carcinogen identification addressed

by short-term tests, to a series of papers in the

April 1979 issue of the Journal of the National

Cancer Institute and to Bartsch et al. (22) about

experiments to validate the reliability of shortterm tests.

Short-term tests are still in their infancy; development of the Ames test began about 15

years ago (11). The major factor influencing the

acceptance or rejection of any short-term test as

a method for identifying carcinogens is a demonstration that the test can discriminate between carcinogens and noncarcinogens.

The crux of validation experiments is determining: 1) how frequently carcinogens are correctly identified by short-term tests (sensitivity)
Ch. 4—Methods for Detecting and ldentifying Carcinogens ● 117

and 2) how frequently noncarcinogens are correctly identified (specificity). Ideally the frequency for both sensitivity and specificity

would be 100 percent. If the Ames test worked

perfectly, every tested carcinogen would be a

mutagen; every tested noncarcinogen would be

a nonmutagen in the test.

The difference between the ideal and the

measured performance can be expressed in

terms of sensitivity. If the test identified 90 of

100 carcinogens as mutagens, it would have a

sensitivity of 90 percent. The same observation

can be described in terms of its false-negative

rate. In the example, 10 carcinogens were falsely

negative in the mutagenicity test, so it had a 10-

percent false-negative rate.

Similarly for noncarcinogens, the test’s success can be expressed as a specificity rate. If it

identified 90 of 100 noncarcinogens as nonmutagens, its specificity was 90 percent. Alternatively, the result can be expressed in terms of the

false-positive rate, which is 10 percent in the

example.

Ames and his associates tested agents that had

been classified as carcinogens or noncarcinogens

in bioassays. They found that 156 of 174 animal

carcinogens (90 percent) were mutagenic, and,

equally important, 96 of 108 (88 percent) chemicals classified as noncarcinogens were not mutagenic (227). Ames has suggested that some of

the “noncarcinogenic” chemicals that were

detected as mutagens might have been incorrectly classified as noncarcinogens on the basis of

bioassay results (11,227). His suggestion points

up a problem inherent in “validating” any test

against the results of other tests: There is no

guarantee that the results of the tests that are

used as standards are completely accurate.

Other researchers have investigated the correlation between Ames test mutagenicity and

animal carcinogenicity in efforts to validate the

mutagenicity test for predicting carcinogenicity.

The good correlation between mutagenicity and

carcinogenicity found by McCann et al. (227)

was “confirmed in a smaller . . . study by the

Imperial Chemical Industries” (34). (In addition,

see for instance 13,22,226,309,335). There is

general agreement that the tests are predictive,

but some disagreement about whether they are

70-, 80-, or 90-percent sensitive. A number of

factors contribute to the observed differences in

sensitivity. For instance, better correlations may

reflect testing chemical classes on which the

Ames test performs well. Ames has shown that

his test does not work well with certain classes

of chemicals, e.g., halogenated hydrocarbons

and metals, and including those in validation

tests decreases the sensitivity of the tests.

Bartsch et al. (22) report on 89 chemicals

studied in the Ames test for mutagenicity. The

89 were chosen because sufficient data existed to

classify each of them as a carcinogen or noncarcinogen in animal tests. Results from the

Bartsch et al. (22) study along with those from

an earlier study by McCann et al. (227) are

shown in table 24.

It can be seen that 76 percent of the tested carcinogens were mutagenic in the Bartsch experiments as compared to the 90 percent that were

reported mutagenic in McCann et al. (227). The

sensitivity in the former study was lower, but

comparable to the other report, The comparison

of specificity is somewhat deceiving. The 57-

percent specificity recorded by Bartsch et al.

(22) is much lower than the 88 percent from the

earlier study, but results from only seven noncarcinogens were reported by Bartsch et al. (22).

McCann et al. (237) tested 108 noncarcinogens.

The 57 percent is subject to much larger error

than the higher estimate of specificity.

In both reports, the predictive value was

found to be over 90 percent. The predictive value is calculated by comparing the number of

carcinogens identified as mutagens to the total

number of both carcinogens and noncarcinogens that were mutagenic. This means that more

than 90 percent of the substances detected as

mutagens were carcinogens.

An important qualifier must be applied to the

predictive value of a test. It depends strongIy

not only on sensitivity and specificity but also

on the proportion of carcinogens in the collection of substances tested for mutagenicity. The

proportion of carcinogens in both validation experiments shown in table 24 was well above 50

percent.
118 ● Technologies for Determining Cancer Risks From the Environment

Table 24.—Results Obtained in Two Validation Studies of the Ames Test When

Known Carcinogens and Noncarcinogens Were Tested

Results from:

Calculation a Bartsch et al. (22) McCann et al. (227)

Sensil ivity C+ M+

760/o (62/82) 900/0 (156/174)

c+ M+ + C+ MSpeciiicity C- M- 570/0 ( 4/7 ) 880/0 ( 96H08)

C- M+ + C- MPredictive value C

+ M+

950/0 (62/65) 920/o (156/168)

C+ M+ + C

- M+

Proportion of C

+ M+ + C+ M- 920/o (82/89) 620/o (174/282)

carcinogens all chemicals tested

a c + ~hemical~ known to be carcinogens; ~ - chemicals known to be noncarclnogens

M + chemicals identified as mutagens; M chemicals identified as nonmutagens

c + M + ~;arcinogens “correctly” identified aS I?IUta9enS

C – M – noncarcinogens “correctly” identified as nonmutagens

C – M + noncarcinogens “incorrectly” identified as mutagens

C + M – carcinogens “incorrectly” identified as nonmutagens

SOURCE’ Office of Technology Assessment, adapted from Bartsch et al. (22)

Table 25 shows the expected results from examining two hypothetical collections of chemicals. The first collection of 1,000 chemicals contains 10 carcinogens (1 percent); the second contains 100 carcinogens in 1,000 total chemicals

(10 percent). The short-term test in both cases is

assumed to be 90-percent sensitive and 90-percent specific. The predictive value in the two

collections differs more than sixfold because of

the higher contribution of false positives to the

total positives in the l-percent carcinogen collection. This example illustrates the important

role played in predictive value computations by

the percentage of carcinogens included in validation experiments.

McMahon, Cline, and Thompson (233) developed a modification of the Ames test and used it

to assay 855 chemicals. To validate their own

test system, the authors included 125 chemicals

that had been tested previously in the Ames test.

They reported “excellent agreement” between

results in their tests and those reported by

McCann et al. (227), Among the other chemicals tested by McMahon, Cline, and Thompson

(233) the 299 chosen from manufacturing or

laboratory synthesis provided the largest percentage of mutagens; 60 of 299 (20 percent) were

mutagenic. In contrast, chemicals developed as

potential agricultural or pharmaceutical products were less often mutagenic; 29 of 361 such

compounds (6 percent) were positive. The

authors state (233):

Very few of the chemical mutagens detected in

this study had chemical structures uniquely different from known carcinogens. Further study in

other test systems will be required to assess the

significance of results with the few unique compounds encountered. The results of the study do

suggest, however, that as testing continues on

more and more compounds it will be found that

most of the new mutagenic compounds detected

will be related to known carcinogens and mutagens and that new unique chemical structures

possessing these properties will be found rarely.

The McMahon, Cline, and Thompson paper

(233) illustrates that large numbers of chemicals

can be tested quickly. Furthermore, their

results, which are in “excellent agreement”

with those earlier reported by McCann et al.

(227) for chemicals tested in both studies, illustrate that the test is reproducible in different

laboratories. Whether the prediction that most
Ch. 4—Methods for Detecting and Identifying Carcinogens ● 119

Table 25.—Expected Results of Examining Two Collections of Chemicals for Mutagenicity Using a Short-Term

Test That is 90-Percent Sensitive and 90-Percent Specific: One Collection of Chemicals Contains 1 Percent

Carcinogens; the Other Contains 10 Percent

Proportion of carcinogens in

sample of 1,000 chemicals

Carcinogens identified as

mutagens

Carcinogens identified as nonmutagens—false negatives in

the test

Noncarcinogens identified as

non mutagens

Noncarcinogens identified as

mutagens—false positives in

the test

Summary:

Carcinogens identified as

mutagens

Noncarcinogens identified as

mutagens

Predictive value— carcinogens

identified as mutagens/total

carcinogens plus noncarcinogens

identified as mutaqens

Calculation a

C+ M+ + C

+ M-

all chemicals tested

C

+ M+

c+ M+ + C+ MC+ M -

C

+ M+ + C+ MC- MC- M- + C- M+

C- M+

c- M- + C- M+

C

+ M+

C

+ M+ + C- M+

Collections of chemicals

with

1 0/0 carcinogens 100/0 carcinogens

1 0/0 (i.e., 10 100/0 (i.e., 100

carcinogens) carcinogens)

90°/0 (i.e., 9 of the 10 900/0 (i.e., 90 of

carcinogens) carcinogens)

10°/0 (i.e., 1 of the 10 100/0 (i.e., 10 of

carcinogens) carcinogens)

~oO/o (i.e., 891 of 990

non carcinogens)

100/0 (i.e., 99 of 990

noncarcinogens)

9

99

108

8.3°\0 (i.e., 9I108)

the 100

the 100

~oO/o (i.e., 810 of ’0 0

noncarcinogens)

100/0 (i.e., 90 of 900

noncarcinogens)

90

90

180

50°/0 (i.e., 90H80)

a c + chemicals known to be carclno9ens; 2 – chemicals known to be noncarcinogens

~ + Chemicals Identified as mutagens, M chemicals identified as nonmutagens

C + M + carcinogens “correctly” Identlfled as mutagens

c – M + noncarcinogens ‘r Incorrectly” Identlfled as mutagens

C

 + M – carcinogens “incorrectly” Identlfled as nonmutagens

SOURCE Office of Technology Assessment, adapted from Bartsch et al (22)

mutagens will have structures related to those of

known carcinogens awaits further testing.

The International Program for the Evaluation

of Short-Term Tests for Carcinogenicity (partially supported by the National Toxicology

Program (NTP), the National Institute of Environmental Health Sciences (NIEHS), and EPA)

is analyzing the accuracy of about 30 short-term

test systems including the Ames test. The program distributed 42 coded carcinogens and noncarcinogens to 66 investigators, and the results

of those studies will be published in 1981. The

accuracy of the Ames test in the 12 laboratories

which examined it is comparable to the higher

accuracy figures (about 80 percent) in the literature (188).

The largest program in genetic toxicology

(mutagenicity) is EPA’s Genetox Program (357).

It is not now engaged in validating short-term

tests for predicting carcinogenicity, but it is examining correlations among various short-term

tests. Beginning in early 1982, the program expects to publish recommendations for batteries

of tests most appropriate for measuring particular mutagenic effects.

How much reliance is to be placed on the

results of short-term tests continues to be
120 ● Technologies for Determining Cancer Risks From the Environment

discussed. Leon Golberg, former President of

the Chemical Industry Institute of Toxicology

(CIIT), for instance, compared the results from

Ames tests to bioassay results for hair dye components. He found little agreement and cautions

against using the Ames test as a substitute for

bioassays (142,143). However, a recent paper

found good correlation between the mutagenicity and carcinogenicity of phenylenediamine hair

dye components (330).

In summary, the Ames test is reported to detect known carcinogens as mutagens with a frequency as high as 90 percent. Although a breakthrough in understanding of the correlation between mutagenicity and carcinogenicity is required before more definitive conclusions can be

drawn from the Ames test, a positive Ames test

result shows that the agent is a mutagen and

suggests that it may be a carcinogen.

Other Short-Term Tests

The number of short-term tests has proliferated rapidly. Purchase et al. (301) included only

six short-term tests in a 1976 review of the published literature; less than 1 year later, OTA had

saccharin tested in 12 short-term tests (282).

Two years after that, in the summer of 1979, a

review by Hollstein et al. (172) reported that

over 100 short-term tests had been described in

the scientific literature. The proliferation of tests

reflects the great interest in cheaper, faster tests

for identifying chemical carcinogens.

Hollstein et al. (172) divided short-term tests

into eight classes, according to what they can

detect:

1.

2.

3.

4.

5.

6.

mutagenesis in bacteria (including Salmonella) and bacterial viruses;

mutagenesis in yeast;

mutagenesis in cultured (laboratorygrown) mammalian cells;

mutagenesis affecting mouse hair color;

mutagenesis in fruit flies (Drosophila melanogaster);

effects on chromosomal mechanics in intact mammals and in mammalian cells in

culture;

7. disruption of DNA synthesis and DNA repair mechanisms in bacteria and other

organisms; and

8. in vitro transformation of cultured cells.

One of the powerful tools available to biology is the use of cell culture systems, which

allows cells obtained from animal or human tissues to be grown and manipulated in the laboratory. Cell cultures can be manipulated to serve

as assays for mutagens (#3 above) and for chemicals that interfere with chromosomal mechanics

(#6 above), but the most directly applicable use

of cultured cells for carcinogen identification involves in vitro transformation (#8 above).

Cells grown in culture exhibit characteristic

morphologies and growth patterns. Exposing

cultured cells to known tumor-causing viruses

or to chemical carcinogens causes changes in

morphology and growth characteristics. The

changes are collectively called “transformation. ” Transformed cells resemble cells from

tumors and have the important property of

causing tumors when they are injected into animals, thus demonstrating a direct relationship

between transformation and oncogenicity (tumor formation). Transformation of cell cultures

is biologically more closely related to oncogenicity than is mutation, and transformation

assays may take on major importance in testing

programs. The NTP 1979 Annual Plan (271)

stated:

A lifetime bioassay in rodents is the current

procedure utilized to determine carcinogenic potential of a chemical. The NTP does not propose

alternative methods but acknowledges a need in

the longer term, to develop or validate less expensive and more rapid methods that may in

some instances supplant the need for lifetime

bioassays. Mammalian cell transformations are

potential short-term assays that indicate carcinogenic potential of a chemical . . .

And less than a year later, a more optimistic

comment appeared in the Department of

Health, Education, and Welfare (DHEW) Health

Research Planning document of December 1979

(130):
Ch. 4—Methods for Detecting and ldentifying Carcinogens ● 121

The dimensions of NTP, and the significant

demands it places on the funds and personnel of

the participating agencies, should diminish by

1985, as the fiscal projections suggest . . . . It is

our hope that, by then, better test systems will

begin to replace the tedious and costly animal

assays now required.

Not everyone is so optimistic as to think a replacement for animal assays will be available in

4 or 5 years. Transformation tests are probably

the best bet for the replacement, but they require more development and validation.

Transformation assays are technically more

difficult than the Ames test, but not so difficult

as to preclude their use on a routine basis.

Validation studies are being carried out on a

number of in vitro transformation systems to

determine how accurately they identify carcinogens and noncarcinogens (271,272).

NTP is conducting additional validation studies of a test that uses whole animals. This test,

which has been in limited use for about 30

years, requires about 6 months to complete. Exposure of a particular strain of mice to known

carcinogens causes an increase in the frequency

of lung tumors (adenomas) and causes earlier

appearance of the tumors. The test takes much

less time than the standard assay, and NTP

(272) has found this test accurately predicts

results in bioassays. NTP tested 60 chemicals in

this system in 1980 and plans to test another 30

in 1981.

The British publication The Economist (97)

singled out a transformation assay, using Chinese hamster ovary cells, as having promise for

carcinogen identification. Discussion of shortterm tests in that publication, which seldom

publishes articles about biology, reflects the increasing importance of the tests. A more authoritative source, the NCI National Cancer Advisory Board’s Subcommittee on Environmental

Carcinogenesis (245) said: “ . . . this subcommittee is enthusiastic about the possible future

use of in vitro [short-term] tests as part of a

screening system for potential carcinogens and

believe that their further development and validation deserve high priority.”

Use of Short-Term Test Results and

Policy Statements About the Tests

How best to utilize short-term tests in carcinogen identification is hotly debated. The majority view is that the tests are most useful as a

screen to determine a chemical’s potential carcinogenicity. As a new chemical is developed or

as an old one comes under suspicion, an inexpensive short-term test or battery of tests can

provide information about whether it is or is not

likely to be a carcinogenic hazard. If the results

of the test are negative, the chemical is considered less likely to be a hazard than a chemical

that is positive. In the case of a chemical being

commercially developed, a positive result might

suggest that the chemical not be produced or

that the cost of testing it in a bioassay should be

considered in deciding whether or not to produce it. A positive short-term test result on a

commercially produced chemical most likely

causes more of a problem. The manufacturer is

faced with having to begin other tests and to

warn his employees and customers of potential

hazard.

Opinions differ about the weight to be placed

on short-term test results. Peter Hutt, former

General Counsel at the Food and Drug Administration (FDA), and now in private law practice

says that he advises his clients not to continue

the development of a product which is positive

in a short-term test. He maintains that, “life is

too short” to invest time and effort in a chemical

that is more likely than not to be considered a

suspect carcinogen. Near the ether end of the

spectrum of opinion, Leon Golberg, in reviewing poor correlations between results of Ames

testing and bioassays of components of hair

dyes, concludes “ . . . it is very hard to accept

the fact that the Ames test is a predictor of carcinogenic potential” (143).

The OSHA document “Identification, Classification and Regulation of Potential Occupational Carcinogens” (279), accepts the results of

short-term tests as supportive evidence for deciding whether a chemical will be classified as a

carcinogen or noncarcinogen. TSCA test stand-
122 Technologies for Determining Cancer Risks From the Environment

ards (106) and Federal Insecticide, Fungicide,

and Rodenticide Act (FIFRA) guidelines (102)

accept short-term tests as measures for mutagenicity but do not consider them in making

decisions about carcinogenicity. However, they

mention that test developments are promising.

An important step in making decisions about

the use of short-term tests are the ongoing

validation studies which compare predictions

made from short-term tests to knowledge about

carcinogenicity from bioassays or epidemiology. These studies, although limited by the quality and quantity of data about carcinogenicity,

are producing valuable information. In addition, studies of molecular mechanisms of mutagenicity and carcinogenicity are important in

deciding about the applicability of short-term

tests.

BIOASSAYS

Chemicals cannot be tested for carcinogenicity in humans because of ethical considerations.

A substantial body of experimentally derived

knowledge and the preponderance of expert

opinion support the conclusion that testing of

chemicals in laboratory animals provides reliable information about carcinogenicity.

Animal tests employ whole mammal systems,

and although they differ one from another, all

mammals, including humans, share many biological features (266):

Effects in animals, properly qualified, are applicable to man. This premise underlies all of

experimental biology and medicine, but because

it is continually questioned with regard to

human cancer, it is desirable to point out that

cancer in men and animals is strikingly similar.

Virtually every form of human cancer has an experimental counterpart, and every form of multicellular organism is subject to cancer, including

insects, fish, and plants. Although there are differences in susceptibility between different animal species, and between individuals of the same

strain, carcinogenic chemicals will affect most

test species, and there are large bodies of experimental data that indicate that exposures that are

The problem of the carcinogens that are not

detected (false negatives; lack of sensitivity) and

the noncarcinogens that are falsely detected

(false positives; lack of specificity) by any one

test might be solved with additional short-term

tests. The great attractiveness of a battery of

short-term tests is that it might correctly identify all carcinogens and noncarcinogens. Unfortunately, no such battery has yet been defined. The composition of the battery will depend on validation studies and acceptance of

each component test.

The growing use of short-term tests shows

that short-term tests have moved to an important position in toxicology. The speed with

which they have been incorporated into Government and private sector programs reflects the

importance of the need to which they are addressed.

carcinogenic to animals are likely to be carcinogenic to man, and vice versa.

In comparison to short-term tests and epidemiology, bioassays have had a longer development period and enjoy greater acceptance than

the short-term tests; they are more easily manipulated to produce evidence linking a particular

substance to cancer than epidemiology, and

they can predict human risks rather than relying

on cases of human cancer to demonstrate risk.

On the other hand, they take longer and cost

much more than short-term tests.

The bioassay’s apparent simplicity belies the

difficulty of executing such experiments. Briefly, the suspect chemical is administered to a

population of laboratory animals. As animals

die or are killed during the course of the study,

they are examined for the presence of tumors.

At the end of the treatment and observation

period (generally about 2 years), the surviving

animals are killed and examined. A control

group of animals is treated exactly the same except that they are not exposed to the suspect

substance. The type and number of tumors and
Ch. 4—Methods for Detecting and identifying Carcinogens ● 123

other relevant pathologies present in the exposed animals are compared with those in the

control group, and statistically analyzed.

A statistical expression commonly used to describe a positive result is “. . . it has a p value

less than 0.05" (5 percent). The p value is the

probability that the observed effect might be explained by chance; in this case, the expression

means that the probability of the observed carcinogenic effect being due to chance is less than

5 percent. A p value of 0.05 or less is commonly

required to decide that a test result was statistically positive.

Finally a conclusion is drawn about whether

or not the evidence indicates that the substance

caused cancer in the exposed animals. An excellent discussion of experimental design and

analysis is available from the International

Agency for Research on Cancer (IARC) (187).

The first successful experimental induction of

cancer in animals (in 1915) showed that painting

rabbits’ ears with coal tar produced tumors

which morphologically resembled human tumors associated with exposure to the same agent

(cited in 342). Most chemicals which are presently known to cause cancer in humans are also

carcinogens in animals.

Verification of the predictive power of bioassays would require that the agent be shown to

be a human carcinogen. Currently, IARC maintains that convincing evidence for human carcinogenicity is available for only 18 exposures,

including 14 chemicals. At the same time, it lists

142 substances for which data are “sufficient” to

conclude that they are carcinogenic in animals.

It is difficult to demonstrate human carcinogenicity. Once a substance is shown to be an animal carcinogen, regulatory restrictions on and

voluntary reductions in the use of the chemical

may reduce human exposures, making those

demonstrations more difficult. Reductions in exposure in such cases are far more important to

human health than the foregone opportunities

to verify the predictive powers of bioassays.

Standard Protocols for Bioassays

An important event in bioassay design was

the development of NCI’s Guidelines for Carcinogenic Bioassay in Small Rodents (33 I). The

guidelines describe minimum requirements for

the design and conduct of a scientifically valid

bioassay and discuss important considerations

in undertaking such studies. They are written to

provide flexibility in experimental design while

setting certain minimal requirements:

1.

2.

3.

4.

5.

6.

7.

Each chemical should be tested in at least

two species and both sexes. Rats and mice

are usually the species of choice.

Each bioassay should contain at least 50

animals in each experimental group.

When both sexes of two species are used

and two treatment levels are administered

and a third group is used as controls, a total of 600 animals is needed (see table 26).

Exposure to the chemical should start

when the animals are 6 weeks old or

younger and continue for the greater part

of their lifespan. Mice and rats are usually

exposed for 24 months.

One treatment group should receive the

maximum tolerated dose (MTD), which is

defined as the highest dose that can be

given that would not alter the animals’

normal lifespan from effects other than

cancer. The other treatment group is

treated with a fraction of MTD.

The route by which a chemical is administered should be the same or as close as

possible to the one by which human exposure occurs.

Animals are closely monitored throughout the study for signs of toxic effects and

other causes affecting their health.

Examination of animals is conducted by

or under the direction of a pathologist

qualified in laboratory animal pathology.

The guidelines also specify that special procedures (e.g., organ function tests, body burden

determinations, absorption and excretion tests)

may be needed for evaluating certain chemicals.
124 ● Technologies for Determining Cancer Risks From the Environment

Table 26.—Distribution and Number of Animals in

a Typical Bioassay Study of Carcinogens

Species A Species B

Experimental groups Males Females Males Females

Dosage MTDa group 50 50 50 50

Dosage MTD/x group 50 50 50 50

Control group 50 50 50 50 — —

aMaxlmum toterated dose.

SOURCE: National Cancer Institute

A National Research Council report (262)

suggested a two-generation bioassay when there

is special concern with prenatal and perinatal effects of a substance. In the suggested two-generation experiment, the first generation is exposed from 6 weeks of age through their adult

life, including periods of reproductive activity

and pregnancy, and the offspring are exposed

for their lifespans. The most important two-generation experiments, from the standpoint of

public policy, were the three showing saccharin

to be a bladder carcinogen in second generation

rats (282). The advantage of the two-generation

experiment is that it exposes fetuses and very

young animals, which may represent the most

sensitive stages of life. This procedure costs

more and requires more time to complete than

the one generation experiment. Probably because of those disadvantages, it has not often

been used.

Table 27 compares some specifics of NCI

guidelines with those proposed by EPA for

testing under FIFRA (102) and TSCA (106). NCI

guidelines state that at least two-dose levels be

tested; EPA requires three test doses. The highest dose, high-dose level (HDL), for TSCA is

defined as being “slightly toxic” and is to be

determined in a 90-day-feeding study to precede

the oncogenicity experiment. The other two

doses are to be fractions of HDL. EPA prefers

the term HDL, which is less specifically defined

than MTD, because of the controversies which

have erupted over defining MTD. Three-dose

levels are proposed by EPA because a review of

many NCI bioassays revealed that tumor incidence was sometimes higher at a dose of

MTD/2 than at MTD because the higher dose

killed some animals before tumors might have

developed. The third-dose level will also provide additional information about the doseresponse curve (102). The text which accompanies the proposed EPA guidelines for carcinogen testing under FIFRA (102) contains additional information about alternative approaches

considered and subsequently discarded for the

guidelines.

Three to five years are required to complete a

bioassay. A subchronic test, to set dose levels,

requiring 2 to 6 months, is followed by an average 24 months of exposure to the agent, and

sometimes an additional 3 to 6 months observation period. Pathological examination of tissues

from the animals and evaluation of the pathological and other data may take an additional

year.

The cost of a bioassay has been variously estimated: NCI estimates about $400,000, TSCA

guidelines (106) estimated $400,000, and EPA

(112) later estimated a range from $390,000 to

$980,000 .

Some changes have been made in protocols

since the NCI guidelines were published, but in

contrast to the situation in spring 1977, when

OTA reviewed carcinogen testing (282), apparently much less confusion and contention now

exist about what constitutes an adequate bioassay. NCI guidelines are for minimal standards; certainly larger populations of animals can

be tested. For very important bioassays, larger

numbers of animals or more dosage groups

might be specified.

Objections to the Usefulness

of Bioassays

Some general aspects of test design are seldom

disputed. Examples of such provisions are the

requirement of a minimum number of animals

in the test groups and that (generally) both sexes
Ch. 4—Methods for Detecting and ldentifying Carcinogen 125

Table 27.—Guidelines for Bioassay in Small Rodents

— —— .- -- NCI (331)a FIFRA (102) TSCA (106)

Endpoint

Study plan:

Animal species

Number of animals at

each dose

Dosages

Dosing regimen

Start

End

Observation period

Organs and tissues to be

examined

Personnel qualifications:

Study director

Pathologist

Animal husbandry

Cost estimate

Carcinogenicity

2, rats and mice

50 males, 50 females

2, MTD

MTD/2 or MTD/4

plus no-dose control

At 6 weeks of age

At 24 months of age

3-6 months after end of

dosing

All animals: external and

histopathologic examination

(ea. 30 organs and tissues)

N.s.

Board-qualified

N.s.

N.s.

Oncogenicity

2, rats and mice

50 males, 50 females

3, MTD

MTD/2 or MTD/4

MTD/4 or MTD/8

plus no-dose control

In utero or at 6 weeks

Mice, 18-24 mos; rats, 24-30

N.s.

All animals: external examination; some animals: pathologic exam of 30 organs

and tissues, other animals,

fewer organs and tissues

N.s.

N.s.

N.s.

N.s.

Oncogenicity

2, rats and mice

50 males, 50 females

3, HDL

HDL/2 or HDL/4

HDL/4 or HDL/10

plus no-dose control

At 6 weeks of age

At 24-30 months of age

N.s.

All animals: external and

histopathologic examination

(ea. 30 organs and tissues)b

Responsibilities detailed

Board-certified or equivalent

Board-certified vet. or

equivalent

$400,000 Y 160,000

Abbreviations: MTD, Maximum tolerated dose, causes minor acute toxlclty

HDL, high dose level, causes some acute tox!clty

N s., not speclfled

a The NC I Guldellnes specify the lndl~ated m,nlmum requirements, Tfley a[lo~ for flexlblllty in experimental design so long as the minimum requirements are met,

b EPA estimates that the 40,000 microscope slldes produced In this examination WIII require more than 3/4 of a year of a pathologist’s time for analysls

SOURCE Off Ice of Technology Assessment

be tested. On the other hand, consensus does

not exist about some aspects of experimental

design, for instance: How high a dose is to be

administered? The policy of the agency that

draws up the guidelines is reflected in what it

says about the arguable aspects of experimental

design. Tomatis (341) has discussed five debated

issues about bioassay.

1. Doses of chemicals to which test animals

are exposed are too high and are not predictive for effects at levels of human exposure.

High doses of suspect carcinogens are necessary to increase tumor incidence to a level that

can be detected in the limited number of animals

used for tests (180). A chemical causing tumors

at a rate of 0.5 percent in the U.S. population

would result in over 1 million cancer cases. But

an incidence of 0.5 percent would very probably

go undetected in the usual test population of 50

male plus 50 female rats or mice. Administration of the chemical at a 10-times higher dose

might increase the response to a detectable level

given comparable sensitivity between the test

animals and humans. High doses are necessary

to increase the sensitivity of the tests, but arguments arise over whether or not a dose is so high

that it is not predictive of what happens at lower

doses.

The biological argument against depending

on results at high doses centers on the contention that such doses may alter metabolism or

cause local irritations or other toxic response

and cause cancer through a pathway that would

not exist at lower doses (60,139,278). A solution

sometimes offered to the problems raised by

high doses is to run bioassays with many more

animals tested at lower doses. The most spectacular attempt at this was the National Center

for Toxicological Research (NCTR) EDO1 study
126 ● Technologies for Determining Cancer Risks From the Environment

which used 24,000 mice and was designed to detect one cancer in 100 animals. Unfortunately,

neither it nor (probably) any experiment can

eliminate the necessity for testing chemicals at

doses significantly higher than those experienced by humans. Even 24,000 is a small

number compared to the number of people exposed to many chemicals.

2. Routes of exposure in animal tests do not

correspond to routes of human exposure.

Chemicals are administered to laboratory animals in either food, water, by inhalation, forcefeeding (gavage), skin-painting, or injection.

Few objections are raised to administration in

food, water, or by inhalation when the chosen

route mimics the route of human exposure.

More objections are raised to gavage, skinpainting, injection, or ingestion when that is not

the normal human exposure route. However,

such methods are sometimes necessary and, furthermore, carcinogens appear to be distributed

throughout the body regardless of the route of

exposure. EPA (106) stipulates that “to the extent possible, route(s) of administration should

be comparable to expected or known routes of

human exposure.” Adherence to such suggestions will reduce the frequency of this objection.

3. Some animals used for testing are so biologically different from humans that results from them have no value.

Choice of animals for bioassays represents a

compromise. Most current guidelines require or

suggest that chemicals be tested in two rodent

species, generally rats and mice. The advantages

of these species are their small size, reducing the

space necessary for housing, short lifespans (2

to 3 years), reducing the time needed for a lifetime study, and a large amount of information

about the genetics, breeding, housing, and

health of these animals. Rats and mice are cheap

to buy, feed, and house, as compared with

larger animals.

Primates are sometimes used for certain toxicological testing. They are certainly more like

humans than rodents but their supply is limited.

They are expensive, live up to 25 years, and require large areas for housing. Despite these difficulties, NCI now maintains about 600 monkeys for carcinogenicity testing at a cost of

about $500,000 per year (2). Dogs are thought

to be between rodents and monkeys in their apparent likeness to humans, but they are more

like primates in costs.

Differences in metabolism, bioaccumulation,

and excretion between rodents and humans

should be considered in interpreting the significance of animal results for humans. There is

no question that further research in the comparative biochemistry and physiology of man

and rodents is necessary, but the comparisons

will ultimately be limited by restrictions on

what can be determined by experimentation in

humans. Moreover, metabolic studies have

shown that most differences between humans

and experimental animals are quantitative

rather than qualitative and support the idea that

animal results can be used to predict human

responses.

4. Some test animals or organs of test animals are exquisitely sensitive to carcinogens, and such sensitivity invalidates use

of results from such animals.

Griesemer and Cueto (146) have analyzed the

results of testing 190 chemicals in the NCI Bioassay Program (see discussion in Expert Review

of Bioassay Results and app. A). They identified

35 chemicals that were “strongly carcinogenic”

in either the rat or the mouse and noncarcinogenic in the other species. Of the 35, 18 were

positive in the mouse and negative in the rat,

and 17 were positive in the rat and negative in

the mouse, which indicates that neither animal

was much more often the sensitive species.

However, 12 chemicals caused mouse liver tumors, no other lesion in the mouse and no lesions in rats. Taken by themselves these results

suggest that the mouse liver is a sensitive organ.

Liver tumors are often found in mice but are

infrequently found in U.S. citizens, although

they occur frequently in human populations in

other parts of the world. Should a chemical that

causes mouse liver tumors be considered a hazard? An approach to resolving the mouse liver

question was to review how predictive such results are for tumors in other animals. Tomatis,

Partensky, and Montesano (343) showed posi-
Ch. 4—Methods for Detecting and identifying Carcinogens ● 127

tive correlation between a chemical’s being

oncogenic in the mouse liver and its being oncogenic either in the liver or at some other site in

rats or hamsters. (Griesmer and Cueto (146)

presented data only from rats and mice, and

some mouse liver carcinogens in their compilation might be positive in animals other than

rats. )

Despite the finding of Tomatis, Partensky,

and Montesano (343) that mouse liver carcinogens were often positive at other sites or in other

animals, IARC (185,187) considers mouse liver

and lung tumors as “limited evidence” for carcinogenicit y. However, OSHA (272) accepts

mouse liver tumors as “indicators of carcinogenicity” if “scientific experience and judgment”

are used in interpreting the data.

Crouch and Wilson (72) have analyzed some

of the NCI Bioassay Program data. They calculated the potency and the standard error associated with potency of a chemical in causing a

tumor at a particular site in either the rat or the

mouse. In their analysis of 35 tested chemicals,

they found that in 31 cases the potency in both

rats and mice agreed within a factor of 10. Their

analysis and similar analysis by Ames et al.

(14), which consider the inherent error in ex-

periments and the sensitivity of experiments,

significantly reduces the number of chemicals

that are positive in one species and negative in

another. However, those analytical methods

have not been generally applied to bioassay

results.

5. Finding benign tumors in test animals has

no value in defining carcinogenicity.

Tumors can be divided into two classes,

benign and malignant. Benign tumors do not

metastasize, the tumor cells remain in contact

with each other and do not invade other tissues

or organs. Malignant tumors can invade other

tissues and metastasize, spreading to distant

parts of the body and causing other tumors.

Both types of tumors are found in experimental

animals.

Hearings on pesticide regulations have been

marked by repeated arguments about the importance of benign tumors. Should benign

tumors found in experimental animals be taken

as evidence that a chemical causes cancer?

The position that a benign tumor may later

become malignant, that the line of demarcation

between benign and malignant is unclear, and

that benign tumors can also be life-threatening

has prevailed in regulatory agencies. Therefore,

no distinction is made in regulatory decisions

between benign and malignant tumors. This is

clearly reflected in FIFRA guidelines (102) and

TSCA test standards (106) in which the endpoint is oncogenicity (tumor causation) rather

than carcinogenicity (which emphasizes malignancy) (see table 27).

Griesemer and Cueto (146) reported no difficulty in deciding between benign and malignant tumors in the NCI Bioassay Program and

that their conclusions about carcinogenicity

were unaffected by including or excluding benign tumors. IARC statements reflect difficulties

in the interpretation of benign tumors. As mentioned above, it considers the occurrence of

some benign tumors as “limited evidence” for

concluding that a chemical is a carcinogen (185).

It also states that “preneoplastic lesions” may

progress to “frank malignancy.” Furthermore,

IARC (186,187) considers that the occurrence of

both preneoplastic and neoplastic lesions in the

same organ strengthens conclusions about carcinogenicit y.

Expert Review of Bioassay Results

In addition to the general objections to

bioassay procedures that have been discussed,

specific objections may be raised to particular

tests. For instance, animals may have been inadvertently exposed to more than one chemical,

to pathogenic micro-organisms, to extreme temperature, or to temporary deprivation of food

or water, any one of which might influence results. Another frequent item of contention is

whether or not a particular pathologic lesion indicates carcinogenicity. Critical reviews can reduce concern that flaws in experimental design

or conduct mar the experiment or bring its results into question.

IARC periodically calls together panels of experts to review the worldwide literature about

the carcinogenicity of particular chemicals or

exposures. The IARC Monograph Program, be-
128 ● Technologies for Determining Cancer Risks From the Environment

gun in 1970, had published reviews of bioassays

of 422 chemicals and processes by 1979. For 60

of the 422 chemicals and processes, IARC was

able to evaluate both human and animal evidence for carcinogenicity. Those 60 are described in the epidemiology section below.

For the remaining 362 chemicals and processes (185),

. . . there was no information available from

studies in humans [but] the IARC was asked repeatedly to consider making an assessment of

the carcinogenic risk for humans which was

based only on animal data.

In response to those requests, the IARC working group recommended (185):

. . . that in the absence of adequate data in humans it is reasonable, for practical purposes, to

regard chemicals for which there is sufficient evidence of carcinogenicity (i.e. a causal association) in animals as if they presented a carcinogenic risk for humans (emphasis in original).

An IARC working group defined five categories of evidence--sufficient, limited, inadequate, negative, and no data—against which experimental data are to be compared (see app.

A). The working group decided that for 142

chemicals there was sufficient evidence, for

about 100 there was limited evidence, and for

the remainder there was inadequate evidence for

carcinogenicity. The IARC exercise is especially

important because it shows that experts from

both the private and public sectors, sitting on

IARC panels, can consider experiments and results and reach decisions about their meaning.

Griesemer and Cueto (146) analyzed the results of NCI's testing 190 chemicals. IARC (185)

and Griesemer and Cueto (146) classifications

of chemicals included 33 chemicals in common.

Analysis of the classification of those 33 (see

app. A) shows that there was good agreement

about the more carcinogenic of the chemicals.

Such agreement lends credence to the idea that

tests carried out in different laboratories and

analyzed by different experts can lead to similar

conclusions about carcinogenicity.

Policy Considerations About Bioassays

General acceptance of bioassays as predictors

of human risk is sometimes obscured by controversies about particular test results. The Federal

Government, in response to controversies arising from testing artificial sweeteners or pesticides, has asked a number of expert panels to

consider bioassay designs, results, and usefulness. In all cases, the panels endorsed bioassays

while reserving judgment about particular tests

and attaching caveats to some results. Table 28

is a listing of some Government-affiliated panels

and reports plus two trade associations, the

American Industrial Health Council (AIHC)

and the Food Safety Council, and a union organization which have commented on bioassays.

The Office of Science and Technology Policy

(OSTP), in the Executive Office of the President

(281) produced a good, brief exposition of methods, a well-crafted list of recommendations

about carcinogen testing, and suggestions for a

Federal carcinogen policy. About bioassays, the

report says,

. . . it would seem prudent to view a positive

test result in a carefully designed and well-conducted mammalian study as evidence of potential human carcinogenicity.

As indicated by the quote, some organizations

urge consideration of experimental design and

execution before drawing conclusions about

carcinogenicity. AIHC (8), in commenting on

OSHA’s (278) proposed cancer policy, endorsed

bioassays as predictors of human risk:

There is agreement further that a substance

which is a confirmed oncogen in two mammalian species should be subject to regulation as a

probable human carcinogen.

All Federal regulatory agencies accept animal

test results as predictors of carcinogenic risk

for humans. The Interagency Regulatory Liaison Group (IRLG) was formed in 1977 to aline

the policies of the Consumer Product Safety

Commission (CPSC), FDA, the Food Safety and

Quality Service of the Department of Agriculture, EPA, and OSHA. IRLG stated (180):
Ch. 4—Methods for Detecting and Identifying Carcinogens ● 129

Table 28-Some Organizations That Have Considered and Endorsed Animal Tests as Predictors of

Human Risk From Chemical Carcinogens

Organization

The Secretary’s (HEW) Committee on Pesticides and

their Relationship to Environmental Health

National Research Council

Office of Technology Assessment

National Cancer Advisory Board, Subcommittee on

Environmental Carcinogenesis

American Industrial Health Council

Food Safety Council

Occupational Safety and Health Administration

Interagency Regulatory Liaison Group

Office of Science and Technology Policy

American Federation of Labor, Congress of Industrial

Organizations, and United Steelworkers of America

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

Publication

Report (325)

Evaluating the Safety of Food Chemicals (259)

Safety of Saccharin and Sodium Saccharin in the Human

Diet (261)

Pest Control: An Assessment of Present and Alternative

Technologies (262)

Principles for Evaluating Chemicals in the Environment

(263)

Food Safety Policy (269)

Cancer Testing Technology and Saccharin (282)

Environmental Contaminants in Food (284)

General Criteria for Assessing the Evidence for Carcinogenicity of Chemical Substances (245)

The Relation of Bioassay Data on Chemicals to the

Assessment of the Risk of Carcinogens for Humans Under

Conditions of Low Exposure (246)

AIHC Recommended Alternative to OSHA’s Generic Carcinogen Proposal (8)

Proposed System for Food Safety Assessment (125)

Identification, Classification and Regulation of Potential

Occupational Carcinogens (279)

Scientific Bases for Identification of Potential Carcinogens

and Estimates of Risks (180)

Identification, Characterization and Control of Potential

Human Carcinogens: A Framework for Federal Decisionmaking (281)

Post-Hearing Brief on OSHA’s Proposed Standard on the

Identification, Classification and Regulation of Toxic Substances Posing a Potential Occupational Carcinogenic

Risk (7)

SOURCE: Off Ice of Technology Assessment.

Evidence of the carcinogenic activity of an

agent can be obtained from bioassays in experimental animals.

and,

Positive results, obtained in one species only

are considered evidence of carcinogenicity. Positive results in more limited tests (e.g., when the

observation period is considerably less than the

animal’s lifetime), but by experimentally adequate procedures, are acceptable as evidence of

carcinogenicity. Negative results, on the other

hand, are not considered as evidence of lack of a

carcinogenic effect, for operational purposes,

unless minimum requirements have been met.

As these quotes show, both AIHC and IRLG

accept bioassays as predictors of potential

human risk. However, they differ in the weight

of evidence each requires. AIHC wants positive

test results in two species before making decisions about carcinogenicity, while IRLG will

consider making a decision on the basis of positive results in one species. Labor organizations

(e.g., American Federation of Labor, Congress

of Industrial Organizations, and United Steelworkers of America (7)) and environmental

groups also consider positive results in a single

animal as sufficient to make a judgment about

carcinogenicit y.

How Many Chemicals Are Carcinogens

in Animal Tests?

The number of chemicals that are carcinogenic in humans or animals is uncertain. A few

estimates have been made, but the bases for the

estimates are poor.
130 ● Technologies for Determining Cancer Risks From the Environment

OSHA (279) states: “Most substances do not

appear to be carcinogenic, ” and uses information from two lists of test results to support the

statement. OSHA cites the study of Innes et al.

(176), which tested 120 industrial chemicals and

pesticides. Eleven (less than ten percent) were

reported to be carcinogenic, 20 were considered

to require further study, and 89 “did not give

significant indication of tumorigenicity. ” A National Academy of Sciences review of pesticides

(262) also drew attention to the low number of

positive results reported in the Innes study. The

small number was judged to be especially significant because of the large number of biologically

active pesticides included in the test. Certain

reservations must be attached to these conclusions. The maximum dose tested and the number of animals used in the experiments were

smaller than now required, and consequently,

the experiments were less conclusive than more

recent ones.

A more direct criticism of relying on the Innes

et al. (176) document as a measure of how many

chemicals are carcinogens is that it was a preliminary report. Based on the complete report

(26), Barnard (21) states that 29 percent of the

tested compounds were carcinogenic.

The second source cited by OSHA (279) is the

seven-volume Public Health Service (PHS) list

of chemicals tested for carcinogenicity (298).

OSHA (279) reported that about 17 percent of

the 7,000 tested chemicals were tumorigenic.

However, OSHA concluded that these data

“overstated the true proportion of carcinogenic

substances in the human environment” because

suspicious chemicals are selected for testing.

Despite such reservations, the Task Force on

Environmental Cancer, Heart and Lung Disease

(339) said:

Of the upwards of 100,000 known chemicals

of potential toxicity, only approximately 6,000

have been tested for carcinogenicity. It is estimated that 10 to 16 percent of the chemicals so

tested provide some evidence of animal carcinogenicity.

To treat the reported 10 to 16 percent of tested

chemicals as carcinogens as a reliable number is

probably an error because many of the 7,000

tests are clearly inadequate when measured

against current testing guidelines. Scientists employed by the General Electric Co. (141a) have

also examined the lists from the seven volumes

(298). Using a relaxed criterion for carcinogenicity “ . . . any listing that reported an

incidence of tumors in the test animals higher

than in the control animals was scored as

‘positive, ’ “ upwards of 80 percent of the listed

chemicals were found to be positive. It is

important to recognize that this relaxed

criterion would not be accepted in any regulatory decision, and it exaggerates the number of

positives. Furthermore, biases toward testing

chemicals that are likely to be carcinogenic and

toward reporting positive results push the

percentage of positives upward.

OSHA (279) had a contractor analyze a list of

2,400 suspect carcinogens compiled by the National Institute of Occupational Safety and

Health (NIOSH). The contractor estimated that

for 570 (24 percent of the total) there were sufficient data to permit initiation of rulemaking to

classify them as category I or 11 carcinogens

under the proposed OSHA policy.

Neither the Innes study nor the PHS list provides information as reliable as that which is

more recently available from NCI, IARC, and

NTP. Fifty-two percent of NCI-tested and reported chemicals were carcinogens (146). Either

“sufficient” or “limited” data existed to classify

about 65 percent of IARC-listed chemicals as

carcinogens (186,344). NTP (273) reported that

252 (including the 190 reported by Griesemer

and Cueto (146)) tests have been completed in

the NCI Bioassay Program. Under conditions of

the tests, 42 percent were positive, 9.5 percent

were equivocal, 36 percent were negative, and

13 percent were inconclusive.

The biases toward testing likely-to-be-positive chemicals cannot be ignored, and the fact

that negative test results are less likely to be

published and included in any compilation (279)

further complicates analysis of lists of tested

chemicals. These factors tend to increase the

percentage of positive chemicals, and consequently may inflate the estimates of the percentages of chemicals that are carcinogens.
Ch. 4—Methods for Detecting and Identifying Carcinogens ● 131

A definitive answer to questions about how Finding more and more chemicals to be carmany chemicals are carcinogens would depend cinogenic in bioassays raises important policy

on testing every chemical, and that is beyond questions and may force a decision to rank carthe capacity of the bioassay system. Tomatis cinogens for possible regulation or voluntary

(341) reported that 828 chemicals were under reductions. It is not apparent how to deal with a

test worldwide in governmental programs in large number of carcinogens without ordering

1975, and that 317 were repeat tests of chemicals them according to their riskiness.

for which, in his opinion, adequate data already

existed. He did not estimate the number of

chemicals under test in private or commercial

laboratories.

SELECTION OF CHEMICALS FOR TESTING IN

BIOASSAYS AND SHORT-TERM TESTS

Tests develop information to aid in making

decisions about chemicals, and the most important step in information development is placing

the chemical on test. Limited testing capacity

makes it necessary to pick and choose among

chemicals. Not all can be tested. The second

NTP Annual Report (272) underlines this point

in discussing bioassays:

It is unreasonable even to attempt to study all

48,000 chemicals in this way. Current known

world capacity permits the initiation of perhaps

300 such chemical tests each year, and the results

published this year are from the tests begun 4 or

more years ago. This capacity—even if financial

resources were not limiting—could be no more

than doubled in the next 5-10 years. At this rate,

it would take an additional 80 years to study all

currently existing chemicals. Further, approximately 500 new chemicals are introduced into

commerce each year, and this would result in an

additional backlog of some 40,000 untested

chemicals.

The same report pinpoints Federal Government

testing capacity:

In carcinogenesis testing the NTP proposes to

start 75 new chemicals on the lifetime carcinogenicity bioassays in fiscal year 80. This is the

same as the level achieved in fiscal year 79 and is

a two-fold increase over the rate of testing prior

to the establishment of the program. [In fact, 50

were started in fiscal year 1980; 30 are expected

in fiscal year 1981. ]

By spring 1980, the

centered its selection

Federal Government had

activities on two programs, the Interagency Testing Committee

(ITC), and the NTP Chemical Nomination and

Selection Committee. ITC recommends chemicals for testing to the EPA Administrator under

jurisdiction of section 4 of TSCA (the ITC list)

and NTP selects chemicals for testing by the

Federal Government. In addition, NCTR and

CIIT have also published criteria for testing

substances.

The Interagency Testing Committee

Section 4(a) of TSCA stipulates that EPA

issue a rule to require testing if an individual

chemical or category of chemicals “may present

an unreasonable risk of injury to health or the

environment . . . or will be produced in substantial quantities and . . . enter the environment in substantial quantities or there is or

may be significant or substantial human exposure. ” The vagueness of such terminology, “unreasonable risk, ” “substantial quantities, ” “significant or substantial human exposure, ” requires EPA to generate interpretations within

scientific, legal, and policy contexts.

Section 4(c) of TSCA established ITC to recommend chemical substances or mixtures which

should be given priority consideration for testing. ITC is composed of eight members, one
132 ● Technologies for Determining Cancer Risks From the Environment

each from EPA, OSHA, the Council on Environmental Quality (CEQ), NIOSH, NIEHS,

NCI, the National Science Foundation (NSF),

and the Department of Commerce.

ITC is to give priority to those chemical substances which are known or suspected to cause

or to contribute to the causation of cancer (carcinogens), mutations (mutagens),- or birth defects (teratogens). The total number of chemical

substances or mixtures recommended for testing

at any one time is not to exceed 50. TSCA specifies that ITC must update, as necessary, the

testing priority list at least every 6 months. The

EPA Administrator is directed to respond to a

chemical’s being placed on the list within 12

months. The Administrator must either initiate

rulemaking to require testing or publish reasons

for not initiating a testing rule.

ITC’s initial selection of chemicals for consideration was made by combining about 20

Government-compiled lists of potentially hazardous substances. Chemicals that did not come

under TSCA’s purview were eliminated from

further consideration, and the remaining substances were ranked against two measures: exposure and biological activity. The bases for determining exposure were explicitly specified by

Congress in section 4(e)(i)(A) of TSCA:

● general population exposure (number of

people exposed, frequency of exposure, exposure intensity, penetrability);

 quantity released into the environment

(quantity released, persistence);

● production volume; and

● occupational exposure.

In general, chemicals which were ranked high

on the exposure scale were further ranked

against biological activity measurements. TSCA

specified the first three factors, and the others

were included because of their significance in

characterizing biological effects (183):

●

●

●

●

●

●

●

carcinogenicity,

mutagenicity,

teratogenicity,

acute toxicity,

other toxic effects,

ecological effects, and

bioaccumulation.

ITC examined the biological activity score

and the individual biological and exposure factors, and weighed the biological scores against

the exposure scores to select chemicals for detailed reviews. After the reviews, chemicals

were recommended to the EPA Administrator

for consideration. A detailed description of the

scoring system can be found in the initial ITC

report to the Administrator of the EPA (183).

As of November 1980, ITC had filed seven reports to the EPA Administrator. Each report has

updated and revised the list of chemicals eligible

for promulgation of test rules under section 4(a)

of TSCA.

Chemical Categories

An important consideration in selecting

chemicals for testing is how to deal with chemical categories or classes. Section 26(c) of TSCA

specifies that any action authorized or required

under the act “may be taken by the Administrator . . . with respect to a category of chemical

substances or mixtures [and] shall be deemed to

be a reference to each chemical substance or

mixture in such category. ” In making its recommendations ITC selected some categories of

chemicals for testing. EPA must determine

whether to evaluate the scientific, economic,

and regulatory consequences of every present or

potential member of a category of chemicals or

to evaluate selected representatives from the

category. If the decision is made to test representatives, EPA has to assess whether it could

“reasonably” extrapolate test results to chemicals within the group that have not been

studied. Some industry representatives have

questioned the validity of using categories for

chemical testing, particularly the categories recommended by ITC. They express concern that it

would be unrealistic to establish a general policy

for choosing which chemicals should be tested

for every possible category. Charles Holdsworth, of the American Petroleum Institute,

recommended that EPA select members of a category once the “metabolic actor” for the group

is determined. Another possible approach

would be to select chemicals of interest because

of exposure or production volume.
Disposition of the ITC List

As of May 1981, 3-1/2 years after completion

of the first ITC list, EPA had issued no final rule

requiring testing of any ITC-identified chemicals. However, EPA (110) in the summer of

1980 proposed its first health effects test rule on

chemicals nominated by ITC. The proposed rule

would require testing of chloromethane and representative members of the category of chlorinated benzenes for oncogenicity and other

health effects. Support documents describing

the reasons for deciding to require testing and

an economic impact analysis of the tests were

also released (110,112). As of April 1, 1980,

draft copies of test rules for four additional

chemicals and groups of chemicals from the 21

identified on the first three ITC lists were available from EPA.

The General Accounting Office (141) reported that EPA estimates it will take 5 years to

issue a final test rule for an ITC-nominated

chemical. That time is required for the agency to

evaluate the published information about the

chemical. EPA further estimates that an additional 4 years will be required for execution of

bioassay and analysis of their results. At a

minimum, then, 9 years will pass between the

decision to test an ITC-selected chemical and

completion of testing. Certainly the long time

between the decision to require testing and the

production of results is of concern to EPA, and

the agency is working to reduce it (141).

There is a suggestion that many ITC-selected

chemicals are currently under test in other arms

of the executive branch. NTP (273) reported

that of 20 single chemicals and 15 classes recommended by ITC (as of April 1980), 16 of the 20

chemicals and representative chemicals from 14

of 15 classes were then under test or scheduled

for test by NTP. NTP (273) did not make a comparison between the types of tests recommended

by ITC and the types of tests being carried out

or planned by NTP. The NTP report draws attention to a problem common to an active field

such as toxicology. ITC judgments about

whether or not to require a test are based or

what it knows about in-progress and completed

tests. It is important that NTP and other testing

organizations share their latest information and

plans with ITC. Accordingly, a liaison representative of NTP attends and participates in ITC

meetings and related activities.

Responsibility for Testing Under TSCA

Once a chemical or category is selected for

testing, EPA must determine who should bear

the responsibility and burden of testing. TSCA

requires EPA to indicate whether manufacturers, processors, or both manufacturers and

processors bear the responsibility. EPA is

presently evaluating exposures that occur at

various points in a chemical’s life cycle. If EPA

finds that the chemical’s manufacture may present a risk, only the manufacturers must test. If

processing may pose a hazard, only the processors are required to test. However, if distribution in commerce, use, or disposal of the chemical may present a risk, both the manufacturers

and the processors are required to test. This

determination has substantial economic and

legal ramifications since it will establish the

universe of firms which must bear the cost of

testing. Some of the chemicals for which test

rules have been drafted are manufactured by

more than one company. EPA is urging that

firms cooperate to sponsor single tests of the

chemicals rather than have each company sponsor its own test.

National Toxicology Program

NTP was established within DHEW (now Department of Health and Human Services

(DHHS)) on November 15, 1978, to further the

development and validation of integrated toxicological test methodologies. The NTP Executive Committee is composed of the heads of

FDA, OSHA, CPSC, EPA, National Institutes

of Health (NIH), NIOSH, NCI, and NIEHS.

NTP’s annual plan for fiscal year 1980 (272)

describes methods to select chemicals for testing: NTP operates under the principle that industry will test chemicals for health and environmental effects as intended and mandated by

Congress under legislative authorities. HOWever, some chemicals will not be tested by the

private sector, and NTP will select chemicals for
134 ● Technologies for Determining Cancer Risks From the Environment

its own testing program from the following

categories:

1.

2.

3.

4.

5.

6.

7.

8.

chemicals found in the environment that

are not closely associated with commercial activities;

desirable substitutes for existing chemicals, particularly therapeutic agents, that

might not be developed or tested without

Federal involvement;

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;

certain chemicals tested by industry, or by

others, the additional testing of which by

the Federal Government is justified to

verify the results;

previously tested chemicals for which

other testing is desirable to cross-compare

testing methods;

“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);

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); and

in special situations, as determined by the

executive committee, marketed chemicals

which have potential for large scale

and/or intense human exposure, even if it

may be possible to require industry to perform the testing.

NTP solicits lists of chemicals from NTP research (NCI, NIEHS, FDA, NIOSH) and regulatory (FDA, OSHA, CPSC, EPA) agencies,

other Federal agencies, academia, industry, labor, and the public. All of the chemicals suggested for study are funneled to the NTP Chemical Nominations Group.

The Chemical Nominations Group, composed of representatives from EPA, OSHA,

FDA, CPSC, NIH, NCI, NIEHS, and NTP, prepares a dossier describing what is known about

the physical properties of each chemical, its production volume, its use, exposures to it, and any

toxicological information, Each chemical is

judged against the chemical selection principles

described above and nominations are forwarded

to the NTP Executive Committee which makes

final decisions about which chemicals to place

on test.

A decision by NTP to test a chemical does not

mean necessarily that the chemical will be

placed on a bioassay program. It may mean that

the chemical will be entered into less expensive,

short-term tests first, and depending on the

results of those tests, subsequent decisions will

be made about whether testing should continue.

The National Center for

Toxicological Research

NCTR, a research arm of EPA and FDA was

established to develop a better understanding of

adverse health effects of potentially toxic

chemicals. NCTR’s research emphasis is on determination of adverse health effects resulting

from long-term, low-level exposure to chemical

toxicants (food additives, residues of animal

drugs, etc.); determination of the basic biological processes involving chemical toxicants in

animals in order to enable better extrapolation

of toxicological data from laboratory animals to

man; and development of improved methodologies and test protocols for evaluation of the safety of chemical toxicants (good laboratory practices, automated data systems, etc.). NCTR

chooses substances for testing from the following categories (271):

1.

2.

substances that have no clear industrial

sponsorship and for which it is determined

that further toxicological data are needed.

Usually these are either food contaminants, GRAS (generally recognized as safe

food additives) compounds, or cosmetic

ingredients.

substances that can act as model compounds in a continuing toxicological

methods development program.
Ch. 4—Methods for Detecting and identifying Carcinogens ● 135

3. substances for which there is a pressing

need to acquire toxicological data above

and beyond that which may be supplied

by industry.

4. studies as a direct regulatory response to

consumer complaints.

Chemical Industry Institute

of Toxicology

CIIT was established in 1974 as an independent, nonprofit research laboratory financed by

annual contributions from the member companies. Membership in CIIT is open to any corporation or other business entity whose activity

consists to a substantial extent of the manufacture, processing, or use of chemicals and any

formal association of such entities. CIIT is to

provide objective study of toxicological problems problems involved in the manufacture,

TIER TESTING

This chapter has so far discussed various test

procedures, from quick, low-cost molecular

structure analysis through relatively quick,

relatively cheap short-term tests to long-term,

high-cost bioassays. The fourth category of test,

epidemiologic studies, differs from the other

three. Detection of a carcinogen because it

causes human illness and death can be regarded

as a failure in hazard identification, because the

other three tests should have or might have predicted the risks before the substance had a

chance to inflict harm.

During the last several years, a number of expert committees and panels have discussed an

ordered approach to testing—proceeding from

quick, cheap tests to longer, more expensive

tests. One such “tier testing” plan was developed by an expert group drawn from academic

institutions, public-interest organizations, industry and Government agencies (66). A repeated criticism expressed in letters that commented on the plan was the absence of criteria

on which to drop a chemical from further testing requirements (66), The point was made that

the tier system developed by the Conservation

handling, use, and disposal of commodity

chemicals.

CIIT has developed a set of criteria to select

and rank chemicals into priority lists for study.

These criteria are:

. volume of production,

● physical and chemical properties,

● estimated human exposure,

● toxicological suspicion and opinion,

● public interest, and

● significance to society.

To date about 40 chemicals have been selected by CIIT for review and study. CIIT’s

testing showed that formaldehyde caused nasal

cancer in rats. Those results have been used by

Federal agencies in considering regulations

about the chemical.

Foundation was actually a sequential test series,

since once a chemical entered the test series it

would apparently continue on through every

test.

Tier testing has no place in regulations of carcinogens under FIFRA and TSCA, since EPA

regulation of substances as a carcinogen requires bioassay or human data (102, 106). To

talk of a tier testing system under those regulations is academic, but evidently EPA is considering a role for short-term tests for making

decisions about carcinogenicity. In the suit

brought by the Natural Resources Defense

Council against EPA because of its failure to act

on the ITC chemicals, Warren Muir of EPA

said: “ . . . EPA is in the process of considering

what kinds of results from short-term tests suggest the need to require long-term tests for the

potential for causing cancer . . . “ (243).

An approach to tier testing appears in the

1980 NTP annual plan and is described in figure

20. The close interrelationships between genetic

toxicology and carcinogenesis test programs are

shown by the lines which connect them. The ab-
136 ● Technologies for Determining Cancer Risks From the Environment

Figure 20.—lnterrelationships of Major Testing Activities of NTP

Phase IV

Phase I Phase II Phase Ill Scientific and Public

Test program Identify toxic potential Confirm toxic effect More definitive result Health Assessment

I I

Genetic toxicology

(mutagenicity)

Sa/nTone//a (Ames) assay (30~EIrosophi/a spp ~ Mammalian assays S

Mammalian cell culture (70) (30) (mouse heritable I I

N 7

translocation)

I

I

I

I Total evaluation

I

Carclnogenesls Cell culture ~ Short-term in _ Lifetime rodent~

of all data

tran:;formatlon wvo (mouse bloassays I

1

lung aaenoma) (75)

~1 i I

Toxicology Rodent toxicology

screen (75)

a( ) ~earlY capacity, fiscal year 19E0 fi9ures.

SOURCE: Off Ice of Technology Assessment, adapted from NTP (272)

-+

I

I

I

sence of arrowheads on the lines is intentional;

according to David Rail, NTP Director (303),

there has not yet been enough experience with

the scheme to be certain which phase I tests

should come first or whether all chemicals

should go through all phase I tests.

A critical feature of tier testing is the ability to

make decisions about whether or not to continue testing from phase I to II, or from 11 to III.

Guidelines are necessary for making the decision that a chemical is sufficiently without risk

and that no further testing is necessary. Rail

(303) said that development of decisionmaking

guidelines is a priority item for NTP in 1980 and

1981. NTP intends to analyze the testing histories of chemicals that have gone through all

three phases (albeit not necessarily under NTP

aegis) to determine which test results were most

predictive of the ultimate decision about the

chemical. NTP will take advantage of the fact

that the most expensive and time consuming

testing, phase III, has been completed on some

chemicals which have not otherwise been tested.

Such chemicals will be entered into phase I and

II testing to provide additional information

about which tests are most predictive. Finally,

the NTP decision to continue testing a few

chemicals that are negative in phase I tests will

provide additional information.

EPIDEMIOLOGY

Lilienfeld (210) defined epidemiology as the exposure to carcinogenic agents or between asstudy of the distribution of disease in human pects of lifestyle and increased cancer risk.

populations and of the factors that influence disease distribution. Epidemiologic techniques are The earliest association of a factor with

useful for identifying causative agents and con- cancer was made by Ramazzini in 1713. He

ditions that predispose for cancer. Studies can found that nuns had a higher rate of breast

determine associations in populations between cancer than other women and, in his Treatie on
the Diseases of Tradesman of 1700, he attributed the increase to celibacy (322). That

association has been sharpened to include the

observation that women who deliver a child at

an early age are less likely to develop breast

cancer. In addition to identifying cancer risks,

epidemiology may play a positive role by pointing out less hazardous diets or agents which are

protective against cancer.

For the purpose of this discussion, epidemiologic studies are divided into three general

types: 1) experimental, 2) descriptive, and 3)

observational. While several basic strategies exist, there are no rigid study designs within any

of these categories. Flexibility is important

since, unlike laboratory experiments, epidemiology examines groups of unpredictable people

living in dynamic environments. The importance of flexibility is underlined by IRLG Guidelines, which state that epidemiologic study

design must “be described and justified in relation to the stated objective of the study” (181).

Experimental Epidemiology

The ideal procedure for investigating causeand-effect hypotheses is through experimental

epidemiology. This type of study requires the

deliberate application or withholding of a factor

and observing the appearance or lack of appearance of any effect. Given the severity of cancer,

ethical considerations preclude the administration of suspected carcinogens to people, though

it is possible to test agents thought to aid in

prevention (292).

Experimental epidemiology studies are difficult to conduct because of the need to secure

the cooperation of a large group of people willing to permit an experimenter to intervene in

their lives. The investigator must have reason to

believe that the proposed intervention, whether

a deliberate application or withholding, will be

beneficial, but at the same time, he must be

somewhat skeptical of the effects. Once sufficient evidence leads to the conclusion that the

intervention is or is not beneficial, the experiment must be terminated.

Descriptive Epidemiology

Descriptive epidemiology studies examine the

distribution and extent of disease in populations

according to basic characteristics—e.g., age,

sex, race, etc. The primary purpose of conducting descriptive epidemiologic studies is to

provide clues to the etiology of a disease which

may then be investigated more thoroughly

through more detailed studies. Descriptive

studies have focused on international comparisons and comparisons among smaller geographical regions, such as U.S. counties (29).

The identification of high bladder cancer rates

in New Jersey males and excess mortality rates

from cancer of the mouth and throat, esophagus, colon, rectum, larynx, and bladder in the

industrialized Northeast have suggested that occupational factors might be incriminated and

have prompted additional investigations. Blot

et al. (29) describe NCI’s stepwise approach to

search for etiological clues. Examination of agespecific rates of disease occurrence or mortality

across time (see ch. 2) is another example of descriptive epidemiology.

Observational Epidemiology

Observational epidemiology depends on data

derived from observations of individuals or relatively small groups of people. These studies are

analyzed using generally accepted statistical

methods to determine if an association exists between a factor and a disease and, if so, the

strength of the association. Often the hypothesis

to be investigated arises from the results of a descriptive study. NCI has embarked on several

observational studies based on findings from

their county-correlation studies. For example,

high rates of lung cancer were found in the

Tidewater Virginia area, and a large study was

initiated which found elevated risk for lung

cancer in shipbuilders and smokers.

Cohort Studies

Two types of observational epidemiology

studies, cohort and case-control studies, differ
138 . Technologies for Determining Cancer Risks From the Environment

in the selection of the population groups for

study.

A cohort study starts with a group of people,

a cohort, considered free of the disease under

study, and whose disposition regarding the risk

factor under consideration is known. Usually

the risk factor is an exposure to a suspect carcinogen or a personal attribute or behavior. The

group is then studied over time and the health

status of the individual members observed. This

type of study is sometimes referred to as

“prospective” because it looks forward from exposure to development of the disease characteristic (210,225). Cohort studies can be either

concurrent or nonconcurrent in design. Concurrent cohort studies depend on events which will

occur in the future, while nonconcurrent cohort

studies rely on past data or past events,

Case-Control Studies

In a case-control study, individuals with the

disease under study (cases) are compared to individuals without the disease (controls) with

respect to risk factors which are judged relevant. Some authors label this study design

“retrospective” because the presence or absence

of the predisposing risk factor is determined for

a time in the past (210,225). However, in some

cases the presence or absence of the factor and

the disease are ascertained simultaneously.

The choice of appropriate controls is rarely

without problems. Often, for practical reasons,

controls are chosen from hospital records. However, they may not be representative of the population, and they therefore may introduce “selection bias,” as discussed by MacMahon and

Pugh (218).

In case-control and cohort studies, the groups

selected should be comparable in all characteristics except the factor under investigation. In

case-control studies, the groups should resemble

each other except for the presence of the disease,

while in cohort studies, the study and comparison groups should be similar except for exposure to the suspect factor. Since this rarely is

possible in practice, comparability between

groups can be improved by either matching individual cases and controls (in case-control

studies) or by standard statistical adjustment

procedures (in either case-control or cohort

studies). Demographic variables, e.g., age, sex,

race, socioeconomic status, are most commonly

used for adjustment or matching.

There are advantages and disadvantages with

both the case-control and cohort studies (see

table 29). Case-control studies tend to be less expensive to conduct, require relatively fewer individuals, and many have been especially useful

in studying cancer. The great advantage of

cohort studies is that they allow observation of

all outcomes, not only those originally anticipated. Bias is somewhat reduced in cohort studies since classification into an exposure category

cannot be influenced by prior knowledge that

the disease exists. In a concurrent cohort study,

it is often necessary to wait many years for the

manifestation of enough disease cases to conduct an analysis. The cost and time of the study

can be reduced if conducted nonconcurrently.

Cohort studies tend to require many more subjects than case-control studies and assignment of

individuals to the correct cohort for analysis is

difficult.

Causal Associations

A pragmatic view of causality is necessary,

particularly when studying complex, multifactorial diseases such as cancer. Analysis of the

association between exposure and disease in an

epidemiologic study depends on tests of statistical significance. However, finding a positive

statistically significant association is not sufficient to conclude a causal relationship. Artifactual and indirect associations must be considered. As MacMahon and Pugh (218) state, "

. . . only a minority of statistical associations

are causal within the sense of the definition,

which requires that change in one party to the

association alters the other. ”

Policy Considerations About

Epidemiology

While short-term tests and bioassays are used

to evaluate a chemical’s carcinogenic potential

in the laboratory, the effect on humans is direct-
Ch. 4—Methods for Detecting and identifying Carcinogens ● 139

Table 29.—Advantages and Disadvantages of Case-Control and Cohort Studies

Type of study Advantages Disadvantages

Case-control Relatively inexpensive Complete information about past exposures often

unavailable

Smaller number of subjects Biassed recall

Relatively quick results Problems of selecting control group and matching

variables

Suitable for rare diseases Yields only relative risk

Cohort Lack of bias in ascertainment of risk factor status Possible bias in ascertainment of disease

Yields incidence rates as well as relative risk Large numbers of subjects required

Can yield associations with other diseases as by- Long follow-up period

product

Problem of attrition

Changes over time in criteria and methods

Very costly

Difficulties in assigning people to correct cohort

SOURCE Office of Technology Assessment

ly assessed by epidemiologic techniques. Wellconducted and properly evaluated epidemiology

studies which show a positive association are

accepted as the most convincing evidence about

human risks.

Negative epidemiologic results show that exposure of a certain number of people to a substance at a specified level did not cause cancer.

From such results, it is possible to calculate that

human risk is no higher than what the study

could have detected. For instance, a study of

1,000 people which showed no excess cancer

would be “more negative” than one of 100 people exposed at the same level. Neither study

would show that a risk exists, and neither shows

that no risk exists, but the larger study shows a

lower probability of risk.

The OSHA Generic Cancer Policy (279) proposed that OSHA, after ascertaining the adequacy of the study design, would interpret

negative epidemiologic studies as setting an upper limit for human risk. AIHC (8) wants negative human evidence to be considered along

with animal data in making decisions about carcinogenicity. The OSHA position, and that of

Federal Government regulatory agencies in general (306), is to use epidemiology to estimate

limits of risk, but not to weigh negative human

evidence against other positive evidence in

deciding whether or not a substance is a carcinogen.

The Regulatory Council (306) considers properly designed and conducted epidemiologic

studies, which show a significant statistical relationship between human exposure to a substance and increased cancer risk, to provide

“good evidence” that a substance is carcinogenic. The Council mentioned some difficulties

in epidemiology, e.g., long latency periods,

multiplicity of exposures, and cautioned that

often “even large increases (which could involve

thousands of people) . . . cannot be detected. ”

For these reasons they cite two caveats in using

epidemiological studies:

The failure of an epidemiological study to detect an association between the occurrence of

cancer and exposure to a specific substance

should not be taken to indicate necessarily that

the substance is not carcinogenic.

Because it is unacceptable to allow exposure

to potential carcinogens to continue until human

cancer actually occurs, regulatory agencies

should not wait for epidemiological evidence

before taking action to limit human exposure to

chemicals considered to be carcinogenic.

OSTP (281) states that “a positive finding in a

well-conducted epidemiologic study can be

viewed as strong evidence that a chemical poses
140 Technologies for Determining Career Risks From the Environment

a carcinogenic risk to humans. ” Alternatively,

“a negative finding is not nearly so meaningful . . . “ and OSTP emphasizes the importance

of examining the sensitivity of a negative study,

and suggests that the upper limit of risk that

might have gone undetected in the study be

calculated and presented.

Carcinogens for Which There Is

Human Evidence

Through various means, epidemiologic studies have identified several human carcinogens.

The first use of epidemiologic principles to

relate environmental contaminants to human

cancer is credited to Pott in 1775 (322). Pott, a

physician in London, suggested that scrotal cancers, which he observed in men who had

worked as chimney sweeps when boys, were

caused by exposure to soot. Pott is an example

of an astute physician recognizing an unusual

cluster of cancer cases. A more recent example is

vinyl chloride which was identified as a carcinogen after three cases of a rare liver tumor

(hepatic angiosarcoma) were diagnosed in

workers in a manufacturing plant (71). In the

case of vinyl chloride, evidence for its carcinogenicity in laboratory animals was available in

advance of the human evidence. In both cases,

control action followed the demonstration of

occupational risk. The Danish Chimney Sweeps

Guild instructed its members about protective

clothing and to practice preventive hygiene soon

after Pott’s report was published, and OSHA

regulated vinyl chloride.

IARC bases its evaluation of carcinogenic risk

to humans on consideration of both epidemiological and experimental animal evidence.

IARC considered human evidence bearing on 60

chemicals and industrial processes and classified

18 as human carcinogens (see table 30). Many of

the human data considered by IARC are from

studies concerning workplace and medical exposure. This does not necessarily reflect the

distribution of carcinogens but more likely the

higher exposure and relative ease of performing

epidemiologic studies on patients and occupational groups. For instance, the availability of

medical records facilitates locating people exposed to a drug and provides information about

time of exposure and dose level.

IARC also classified 18 additional compounds

as probably carcinogenic for humans but there

was insufficient evidence to establish causal

associations. These 18 were further subdivided

according to the degree of evidence, high or

low, as displayed in table 30. Insufficient evidence was available to decide about the carcinogenicity of 18 chemicals listed in table 30.

Finally, because of time limitations, IARC was

unable to evaluate six compounds for which

human data exist.

Annual Report on Carcinogens

In an effort to provide information on carcinogens which would be useful to regulatory

agencies, Congress passed an amendment to the

Community Mental Health Act (Public Law 95-

622). It requires the Secretary of DHHS to publish an annual report containing a list of substances which are known to be carcinogens or

may reasonably be anticipated to be carcinogens and to which a significant number of persons residing in the United States are exposed.

The task was assigned to NTP, and the first report (82) includes the 26 exposures which IARC

had determined in 1978 to be human carcinogens (344). Candidates for the 1981 and 1982 list

also will be drawn from IARC beginning with

chemicals and processes judged “probably carcinogenic for humans. ” The initial report did not,

as required by the statute, list “ . . . all substances which either are known . . . or . . .

may reasonably be anticipated to be carcinogens . . . . “

One limitation enumerated in the first report

was that, “Science and society have not arrived

at a final consensus on the definition of carcinogen either in human populations or in experimental animals. ” The report, by including

chemicals and industrial processes already classified by IARC, has sidestepped dealing with the

question of what is a carcinogen. A definition

for “carcinogen” remains elusive unless it is

given in the context of a particular methodology.
Ch. 4—Methods for Detecting and Identifying Carcinogens ● 142

Table 30.—Chemicals and Industrial Processes Evaluated for Human Carcinogenicity by the International

Agency for Research on Cancer (IARC)

Chemicals and processes judged carcinogenic for humans

4-aminobiphenyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . c .. ..0. “ 0. “ . . P “ 0. “ . ~ . .

Arsenic and certain arsenic compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . “ . . .

Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 0..... . . “ 0.0 “ “ ..0. “ 0. “ ..0.

Manufacture of auramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.0 “ . . . “ . “ 0 . . . .

Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........”.”....” ““””.””.””.”.

Benzidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ““.......””.”.”..”..”” “.

N,N-bis (2-chloroethyl)-2-naphthylamine (chlornaphazine) . . . . . . . . . . . . . . . . . . . . . . . . . . .

Bis(chloromethyl)ether and technical grade chloromethyl methyl ether . . . . . . . . . . . . . . . . .

Chromium and certain chromium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......

Diethylstilboestrol (DES). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......”..”..”.”” .“.

Underground hematite mining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........”””.””.. ““

Manufacture of isopropyl alcohol by the strong acid process . . . . . . . . . . . . . . . . . . . . . . . . .

Melphalan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....,.-.”.”..”..””” “...”..”.*.o

Mustard gas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .“..”””.o”c”.”.””.”.o

2-naphthylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........”.”...””. “...”...’”<

Nickel refining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ““”..””....”.. -.

Soots, tars and mineral oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....””...”..”.””

Vinyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...”....”..”””..”’””. “.

Chemicals and processes judged probably carcinogenic for humans

Group A: Chemicals and processes with “higher degrees of evidence.”

Aflatoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......”...”””. .“’””..”....””... “..

Cadmium and certain cadmium compounds . . . . . . . . . . . . . . . . ...........”...” ...”...

Chlorambucil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .“......”...”””- ..””.

Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”.”.......”..”

Nickel and certain nickel compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ . . . . .

Tris(1-aziridinyl)phosphine sulphide (thiotepa) . . . . . . . . . . . . . . ..;.... . . . . . . . . . . . ..”

Group B: Chemicals and processes with “Iower degrees of evidence.”

Acrylonitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....’.”.”...”..”.. “..”.”....””””

Amitrole (aminotriazole) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...”..”....

Auramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........”,..’’... ....”.....

Beryllium and certain beryllium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Carbon tetrachloride . . . . . . . . . . . . . . . . . . . . . . ................o....o .“..””..””....

Dimethylcarbamoyl chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........”.””.” ....

Dimethylsulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......”......”.”””.”. .

Ethylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”.”.....””.”.......”

Iron dextran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....”,........... ““.”””.”.”..”

Oxymetholone . . . . . . . . . . . . . . . . . . . . . . ........o.o.....”’”o.”. “.”..””..”...”..- ..

Phenacetin . . . . . . . . . . . . . . . . . . . . . . ..........,.,”....”.. ....”..”..””””.”.””””. “

Polychlorinated biphenyls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....”........... ...”.

Degree of evidence

Experimental

Humans animals

Sufficient Sufficient

Sufficient Inadequate

Sufficient Sufficient

Sufficient Nonapplicable

Sufficient Inadequate

Sufficient Sufficient

Sufficient Limited

Sufficient Sufficient

Sufficient Sufficient

Sufficient Sufficient

Sufficient Nonapplicable

Sufficient Not applicable

Sufficient Sufficient

Sufficient Limited

Sufficient Sufficient

Sufficient Nonapplicable

Sufficient Sufficient

Sufficient Sufficient

Degree of evidence

Experimental

Humans animals

Limited Sufficient

Limited Sufficient

Limited Sufficient

Limited Sufficient

Limited Sufficient

Limited Sufficient

Degree of evidence

Experimental

Humans animals

Limited Sufficient

Inadequate Sufficient

Limited Limited

Limited Sufficient

Inadequate Sufficient

Inadequate Sufficient

Inadequate Sufficient

Limited Inadequate

Inadequate Sufficient

Limited No data

Limited Limited

Inadequate Sufficient

Chemicals and processes that could not be classified as to their carcinogenicity for humans

Degree of evidence

Experimental

Humans animals

Chloramphenicol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ““”..”””. Inadequate No data

Chlordane/heptachlor . . . . . . . . . . . . . . . . . . . . . . . . . . . ........c....o.”0”..o”.. .“.”””. Inadequate Limited

Chloroprene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....”’”””..”..””.”””.. Inadequate Inadequate
—.

142 ● Technologies for Determining Cancer Risks From the Environment

Table 30.—Chemicals and Industrial Processes Evaluated for Human Carcinogenicity by the International

Agency for Research on Cancer (IARC) (Continued)

Chemicals and processes that could not be classified as to their carcinogenicity

Degree of evidence

for humans—continued Experimental

Humans animals

Dichlorodiphenyl trichloroethane (DDT). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . . . . . . . . . . .

Hematite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hexachlorocyclohexane (technical grade HCH/lindane). . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Isopropyl oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lead and certain Iead compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenobarbitone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

N-phenyl-2-naphthylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenytoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Reserpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tris(aziridinyl)-para-benzoquinone (triaziquone) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Inadequate

Inadequate

Inadequate

Inadequate

Inadequate

Inadequate

Inadequate

Inadequate

Limited

Inadequate

Limited

Inadequate

Inadequate

Inadequate

Inadequate

Limited

Limited

Limited

Negative

Limited

Limited

Inadequate

Sufficient (for

some soluble

salts)

Limited

Inadequate

Limited

Inadequate

Limited

Limited

Limited

Chemicals and processes for which human data are available, but which were not considered by the IARC Working Group

Ortho-and para-dichlorobenzene

Dichlorobenzidine

Phenylbutazone

2,3,7,8-tetrachlorodiberzo-para-dioxin (TCDD, the ’’dioxin” of Agent Orange)

Ortho-and para-toluidine

Vinylidene chloride

SOURCE: Office of Technology Ajsessmen~ adapted from IARC (185)

SOURCES OF EPIDEMIOLOGICALLY USEFUL DATA

Three major types of information are useful

in assessing the carcinogenic risk of a substance:

l) health status of exposed and unexposed populations; 2) exposure data; and 3) physical,

chemical, and biological properties of the substance. Information related to each of these categories can come from a variety of sources and

can be used in different ways. Testing the substance generates information about its potential

hazard, but information about its distribution in

the environment and any impacts on human

health are necessary to describe its human risk

Health Status Information

DHHS is primarily responsible for administering health data collection, storage, and analysis projects. An overview of existing DHHS

programs and other departments’ health data

collection activities can be found in Selected

Topics in Federal Health Statistics (283).

National Center for Health Statistics

The National Center for Health Statistics

(NCHS) located within the DHHS Office of

Health, Research, Statistics, and Technology,

was established to collect and disseminate data

on the health of Americans. Since 1960, it has

played a major role in the development of national health statistics policy and programs. The

NCHS Division of Vital Statistics collects infermation on natality, mortality, marriage, and

divorce from the individual states and regions.

(See ch.2 for a discussion of cancer mortality

and incidence statistics.) In addition to vital

statistics, NCHS conducts several general-purpose surveys that provide statistics about the

health status of the U.S. population. Additional

information can be obtained from Data Systems

of the National Center for Health Statistics

(253).
Ch. 4—Methods for Detecting and Identifying Carcinogens ● 143

Health Interview Survey (HIS) .–HIS is the

principal source of information on the health of

the civilian noninstitutionalized population of

the United States. Initiated in 1957, interviews

are conducted each week in a probability sample of households to provide data on a range of

health measures, including the incidence of illness and accidental injuries, the prevalence of

diseases and impairments, the extent of disability, and the use of health care services. Each

year, approximately 40,000 households containing about 120,000 persons are sampled.

HIS collects information only about conditions which respondents are willing to report.

The basic questionnaires are similar from year

to year but supplemental questions may be

added. In 1978 and 1979 questions on smoking

were added, but these were discontinued in

1980.

The NCHS Study of Costs of EnvironmentRelated Health Effects, mandated by Public Law

95-623, may use HIS as a data source (179).

Health and Nutrition Examination Survey

(HANES).–HANES, initiated in 1970, is a

modification and expansion of the earlier Health

Examination Survey (HES). These surveys collect and use data from interviews and physical

examinations to estimate the prevalence of

chronic diseases, establish physiological standards for various tests, determine the nutritional

status of the population, and assess exposure

levels to certain environmental substances. The

sampling techniques employed provide representative national data. Two surveys, HANES

I (1971-75) and HANES II (1976-79) have been

conducted. Both surveys examined approximately 20,000 persons.

HANES is the most extensive national assessment of health and nutritional status of the

American people. The nutritional component of

HANES includes: information on dietary intake; data from hematologic and biochemical

tests; body measurements; and chemical examination for various signs of high risks of nutritional deficiency. Preliminary findings from the

HANES II pesticide monitoring program have

found an apparent rise in tissue levels of DDT

and PCBs. The implications of the observed

levels are uncertain.

HANES surveys might become valuable

sources of information for cancer epidemiology

if sufficient resources were available. Because of

its representative nature, aggregate data from

the survey can be used to represent “normal” or

background levels. For example, white cell

count levels determined in HANES I were used

for comparative purposes in an epidemiologic

study of laboratory workers exposed to suspected toxic chemicals. HANES II contains certain information about dietary intake of substances which have been associated with a lower

risk of cancer, vitamins A and C, and substances such as fats which are associated with

higher risks.

HANES might be linked with other health

data systems, such as the National Death Index

(see below) to facilitate assessment of whether

particular exposure levels or certain nutritional

statuses were associated with cancer mortality.

NCHS, with its HANES capabilities, has been

asked to participate in studies near Love Canal,

and to evaluate the health status of certain highrisk industry groups. It was unable to do so

because of limited resources.

The NCHS overall monitoring survey budget

for fiscal year 1981 is $28 million. This is a $3

million increase over 1980 and includes $1.1

million for a special HANES study which will

focus on Hispanics in selected areas of the

United States. The study is designed to describe

the health and nutritional status of the MexicanAmerican, Puerto Rican-American and CubanAmerican populations. Studies of specific

groups are necessary to acquire data in sufficient detail to describe subgroups of the population which differ from the “average.” General national surveys such as HANES I and II

produce data about the “average” citizen by

sampling groups in proportion to their representation in the total population, and this often

results in too small a sample size to be useful for

identifiable smaller groups.
144 ● Technologies for Determining Cancer Risks From the Environment

As examples of data useful for cancer studies,

the HANES Hispanic study will determine:

● name, date of birth, and social security

number recorded in machine readable form

for subsequent use with the National Death

Index;

● history of toxic substance exposure;

● nutritional status including dietary interviews, serum vitamin A levels, prevalence

of vitamin C deficiencies; and

 the quantity and frequency of alcohol consumption.

Hospital Discharge Survey .—This survey

was established in 1964 to provide representative statistics for the U.S. population discharged

from short-term hospitals. The survey collects

information on the characteristics of patients,

the lengths of stay, diagnosis and surgical operations, and patterns of use of care. Completion

of each medical abstract form is estimated to

take approximately 5 minutes. Only short-stay

hospitals with six or more beds and with an

average length of stay of less than 30 days are

included in the sample (177).

Vital Statistics Followback Surveys. —NCHSconducted mortality “followback” surveys have

provided information on possible relations between environmental and lifestyle factors and

death from cancer. Information is sought about

decedents through inquiries addressed to those

providing information for the death certificate,

such as the medical certifiers, funeral directors,

and family members. These surveys are an efficient means to augment the routinely reported

information contained in the vital records.

The efficiency of the followback approach for

eliciting additional information about deaths is

related to the relative rareness of death as an

event in the U.S. population. About 1 percent of

the population dies annually; and cancer-related

deaths are reported for about 20 percent of this

1 percent, or a total of 0.2 percent of the total

population. The followback approach permits

sampling directly from the file of those death

certificates of interest in order to supplement

existing information.

Mortality followback surveys were conducted in the United States annually from 1961

through 1968. They have since been discontinued due to inadequate resources, including

personnel.

National Death Index (NDI).—Deaths in the

United States are registered by the States or

other death registration areas (e.g., District of

Columbia). The records are transmitted on microfilms or on magnetic tape to NCHS for compilation. Historically, because there was no integration of records for the country as a whole, no

mechanism had existed at the national level to

determine if a person had died. In 1981, after

several years of planning and preparation, the

NDI will be placed into operation to serve that

purpose. The NDI will code deaths that occurred in 1979 and each year thereafter. Although there has been discussion of coding

deaths that occurred before 1979, no plans are

now in place to do so.

NDI, administered by NCHS, is designed to

provide medical and health researchers with

probable fact of death, the death certificate

number, and the location of the death certificate, when supplied with a minimum set of identifiers (generally the person’s name and social

security number or date of birth). The researcher then may contact the registration area

where the possible match has occurred to obtain

the death certificate or the required information.

NDI will be of immediate use in ongoing longterm studies which include mortality. Beebe (23)

described the NDI as the most important recent

advance in making vital statistics accessible to

researchers. NCI’s Surveillance, Epidemiology,

and End Results (SEER) program plans to use

the NDI to determine deaths of all persons in the

SEER registries. This should reduce the number

of people lost to followup by SEER and provide

better information about survival. Currently,

deaths of people who moved or cease to participate are not always recorded by SEER.

National Cancer Institute

NCI, 1 of 11 research organizations of NIH,

receives more than one-fifth of all Federal health

research funds (283). NCI operates the SEER

program, which provides cancer incidence data
on approximately 10 percent of the population.

Additional information on the SEER program

can be found in chapter 2.

Centers for Disease Control

The overall mission of the Centers for Disease

Control (CDC) (56) is “to prevent unnecessary

illness and death and to enhance the health of

the American people. ” CDC serves as a focus

for DHHS efforts in the areas of disease prevention and control, environmental health, health

promotion, and health education.

NIOSH, located within CDC, assists OSHA

in establishing workplace health standards. Between 1972 and 1974, NIOSH conducted the

National Occupational Hazard Survey (NOHS)

to provide estimates of the proportion of employees exposed to potential health hazards in

various industries. NOHS estimates of exposure

are often used in assessing risks from occupational carcinogens. NIOSH periodically conducts studies to identify the health effects of particular industrial processes and to determine the

health experience of selected employee populations. The National Surveillance Network,

which is operated by NIOSH, collects data from

State safety and health inspection programs.

Social Security Administration

The Social Security Administration (SSA)

collects information on economic and demographic data in administering the social security

system. SSA makes available an annual l-percent continuous work-history sample (CWHS)

to outside users which provides information

about employment, migration, and earning

status. Six different types of files, all of which

contain sex, race, and age data, are available to

outside users. For purposes of confidentiality,

the employee and employer identification are

included in scrambled form. The usefulness of

the CWHS for epidemiologic studies is limited

by privacy constraints of access and other characteristics, e.g., only wages UP to the taxable

maximum are reported.

SSA has recently initiated efforts to amass a

10-percent sample of the work force because of

the Office of Management and Budget’s (OMB)

need for better estimates of intercensal population. This file would constitute the most detailed

information on the structure of the labor force

so that employment distributions by sex, race,

age, wages, and wage changes, work force participation, industry, and regional migration patterns could be analyzed systematically.

The Disability Insurance Fund, managed by

SSA, contains information regarding benefit

computation and actions related to employee

entitlement. SSA routinely prepares reports regarding specific disease entities and has published characteristics of workers disabled by

cancer (283).

Exposure Data

The principal data deficiencies for assessing

cancer risks are inadequate information about

exposures and lifestyle characteristics. Since

cancer has a long latent period, relating cancer

in today’s population to particular exposures

might require information from 20 or more

years ago. Even when information was collected, records may have been destroyed before

they became useful in cancer epidemiology

studies.

As the lead agency for regulating chemicals,

EPA administers numerous exposure-monitoring programs. Several studies have been critical

of EPA’s monitoring data collection efforts, and

as a result, EPA established a Deputy Assistant

Administrators Committee to review and make

recommendations regarding agency monitoring

and information management activities (113).

Three of the major conclusions found by the

committee are:

1.

2.

3.

A considerable quantity of collected ambient environmental information has not

been analyzed or presented to top management.

The most serious problem found was the

lack of consistent, integrated information

on toxic and hazardous pollutants.

There is little coordination between EPA

offices focusing on the same area. In addition, there is a lack of comparability and

sharing of these data.
146 ● Technologies for Determining Cancer Risks From the Environment

Exposure data in the workplace are limited

even though a number of cancer causing agents

have been identified in the occupational environment. NIOSH’s National Occupational Hazard Survey collects exposure data in a sample of

industries, and OSHA requires monitoring for 6

of the 20 substances regulated because of carcinogenicity.

Death certificates generally include questions

on the usual occupation and industry or business of the decedent, However, those questions

are not always answered and there is uncertainty about the accuracy of the information that is

provided. NCHS, along with NIOSH, is currently assessing the feasibility of using and improving occupational descriptors on death certificates as a surrogate for exposure information. Approximately a dozen States now

code the usual occupation of the decedent, and

about half of these also code the reported usual

industry or business of the decedent. One State,

Wisconsin, now publishes such tabulated information in their annual public health report.

Other States, with support from NIOSH, have

executed special studies on occupational mortality based on data reported on the standard

death certificate (45,236).

In England, information reported on the

death certificate has been used as a basis for occupational mortality analyses every 10 years

since 1851 (with the exception of the war year,

1941). In the United States, a study of this type

was conducted in 1950. It involved coding over

300,000 death certificates for the occupation

and industry of males aged 20 to 64. The information was used in conjunction with the decennial census information for that year to produce measures of relative mortality risk associated with occupation and industry of decedents

(148,149,150,151,196).

The National Human Adipose Tissue Monitoring Program and HIS and HANES, which are

described above, are the principal mechanisms

for monitoring levels of toxics in the body. This

information is used not only to determine normal baseline levels but also to identify populations which may beat high risk.

This assessment did not concentrate on monitoring methods and programs, but the general

impression is that data collection efforts are incomplete and that many generate data of limited

usefulness. For instance, measurement techniques are not always specified for collected exposure data and ignorance of the sensitivity of

the instrument used makes it difficult to compare measurements from different times and

sites. Furthermore, a nondetectable measurement does not necessarily indicate that a substance is not present, and may mean only that

the instrument was not sufficiently sensitive to

measure it. Such negative readings are often not

reported, and when they are, they may be misleading. The efforts of organizations such as the

EPA Committee (113) mentioned above to improve collection and analysis of monitoring

data might be encouraged.

Chemical Information Systems

The lack of toxicological information about

many substances and concern over perceived

toxic substance problems prompted Congress to

enact more than two dozen statutes dealing with

toxics. Many of the statutes delegate information-gathering functions to Federal regulatory

and research agencies.

Toxic Substances Control Act —TSCA

In 1976, Congress passed TSCA to strengthen

the ability of the Federal Government to accumulate information on potentially hazardous

chemicals and better enable the Federal Government to protect the public from toxic substances. TSCA required the establishment of

several new programs at EPA and a completely

new infrastructure had to be organized. This

necessitated recruiting an Assistant Administrator and placed a large burden on a small

staff. Subsequently, the programs have been

slow to get off the ground (141). Recruitment

has continually lagged behind authorized staff

ceilings which may be inadequate to meet expected program needs. EPA estimated that approximately 1,500 people were needed in fiscal

year 1979: 382 permanent positions were authorized, 313 were actually filled.
Ch. 4—Methods for Detecting and ldentifying Carcinogens ● 147

New Chemicals. —One of TSCA’s primary

objectives—as stated in the opening paragraph

of the Committee on Interstate and Foreign

Commerce Report (165), is to provide “for the

evaluation of the hazard-causing potential of

new chemicals before commercial production

begins.” TSCA requires manufacturers and importers to notify EPA at least 90 days prior to

the manufacture or import of a new chemical

substance by submitting a premanufacture notice (PMN). Along with notification, manufacturers are to provide specific information about

the new chemical, including any test data which

relate to the effects of the substance on human

health or the environment. “New” is synonymous with not being listed on the inventory of

existing chemicals and subject to TSCA’s authority. In May 1979, EPA (105) issued a statement of interim policy covering submission and

review of PMNs. Final PMN rules have yet to be

issued. In the 2-year period, April 1979 to

March 12, 1981, EPA received 488 PMNs, and

about 800 are anticipated in fiscal year 1982.

TSCA was not the first Federal law to require

a review of new chemicals entering the market.

FIFRA and the Food, Drug, and Cosmetics Act,

have registration/certification provisions for

pesticides and pharmaceuticals respectively.

Unlike those laws, TSCA requires neither licensing nor registration, but only notification of

intent to manufacture. As mentioned, the PMN

must contain any test data available to the submitter, but EPA cannot require testing of a new

chemical substance just because it is “new. ” The

act places the burden of proof on EPA to demonstrate that the information available to EPA:

. . . is insufficient to permit a reasoned evaluation of the health and environmental effects of a

chemical substance . . . and . . . [that] in the

absence of sufficient information . . . [the substance] may present an unreasonable risk or will

be produced in substantial quantities, and there

may be significant or substantial exposure.

If such a finding is made, EPA may issue an

order under section 5(e) to prohibit or limit the

manufacture, processing, distribution, use, or

disposal of the chemical. EPA has proposed two

such orders and each time the company withdrew its notice and decided not to manufacture.

On two other occasions notices were withdrawn

when the companies learned orders to require

more information were in preparation.

Lack of regulatory action on a new chemical

by EPA does not imply that the substance is

“safe” or has been “approved. ” However, it does

grant the manufacturer the right to produce and

use the chemical as desired, subject to any other

regulations that may be applicable. Under section 5(a)(2) EPA can issue a “significant new use

rule” (SNUR) for a chemical when there is concern that a specific use of the substance, other

than those proposed in the PMN, may pose an

unreasonable risk. Issuance of an SNUR requires that persons must notify EPA 90 days

prior to manufacture or processing of a substance for a use subject to a SNUR. Through

March 1981, one chemical specific SNUR had

been proposed and EPA was considering SNURs

on more than 40 chemicals. Once a substance is

in production, EPA can require testing under

TSCA section 4 and/or submission of human

health and environmental monitoring data under a TSCA section 8 rule (see Existing Chemicals).

EPA recently published a policy statement describing a recommended list of premanufacture

tests for new chemical substances (114). The

tests are identical to those under consideration

by the Organization for Economic Cooperation

and Development (OECD). OECD considers

that its base set of tests would generate the

minimum amount of information normally sufficient to perform an initial hazard assessment

of a chemical (see table 31). EPA is recommending that flexibility be used by manufacturers to

tailor this “base set” of tests for the particular

chemical substance and intended uses. Use of

this base set is voluntary due to EPA’s lack of

statutory authority to require testing of new

chemical substances. The estimated costs of this

base set, should all tests be employed, range

from $53,000 to $67,850.

EPA has reported that no toxicity data were

submitted in 60 percent of the first 199 notices

received (141). In fact, 25 percent of the notices

contained no data on physical or chemical properties. No chronic test data have yet to be
148 ● Technologies for Determining Cancer Risks From the Environment

Table 31.—EPA’s Recommended Base Set of Data

To Be Included in Premanufacturing Notices

Type of data Estimated cost

Physical/chemical data

Data about 11 characteristics . . . . . . . . $ 3,800

Acute toxicity data

Acute oral toxicity. . . . . . . . . . . . . . . . . . 2,000

Acute dermal toxicity . . . . . . . . . . . . . . . 2,800

Acute inhalation toxicity . . . . . . . . . . . . - 3,300

Skin irritation. . . . . . . . . . . . . . . . . . . . . . 700

Skin sensitization . . . . . . . . . . . . . . . . . . 3,200-6,700

Eye irritation (for chemicals showing

no skin irritation). . . . . ., . . . . . . . . . . . 450

Repeated dose toxicity data

14-28 day-repeated dose test(s) using

probable route(s) of human exposure. . 10,200-12,800

Mutagenicity data

Gene (point) mutation data . . . . . . . . . . 1,350

Chromosomal aberration data . . . . . . . 18,000

Ecotoxicity data

Data about killing of three lower

organisms . , . . . . . . . . . . . . . . . . . . . . . . 4,100

Degradation/accumulation data . . . . . . . . 3,100-11,850

SOURCE Office of Technology Assessment, adapted from EPA (I 14)

presented to EPA in a PMN. In cases where toxicity data are given they are usually limited. The

then-Assistant Administrator for Toxic Substances has indicated (192) that the lack of test

data:

. . . has placed an extraordinary burden on

EPA’s limited resources . . . . Furthermore, we

[EPA] believe that our objective will not be

achieved until industry assumes more of the

burden of generating adequate risk information

and assessing the risk of its products.

Unless additional information is received with

the notices, EPA’s reviews will be “based upon a

fundamental lack of information and data. This

in turn means that our information will be highly uncertain” (192). In order to evaluate a chemical’s carcinogenic potential, EPA staff have had

to rely on structure activity relationships and

mutagenicity data when available.

Existing Chemicals, –Sections 4 and 8 of

TSCA relate directly to the issue of acquiring

adequate information for assessing the carcinogenic risk of existing chemicals.

Section 4 grants EPA the authority to require

industry testing of a potentially harmful chemical if available information is insufficient for a

reasoned evaluation of risk and if the substance:

1) may present an unreasonable risk or 2) result

in substantial or significant exposure. TSCA established ITC to recommend chemicals for testing under section 4; ITC and EPA responses to it

are described above. To require industry testing, EPA must demonstrate that available information is insufficient to conclude that the

substance “presents an unreasonable risk, ” yet

supports the finding that the chemical “may present an unreasonable risk. ” If available information were sufficient to show that the chemical

presents an unreasonable risk, EPA could regulate the substance under section 6 of TSCA.

One difficulty EPA faces in using this testing authority is how to define “may present an unreasonable risk. ”

Section 8 of TSCA required EPA to compile

by November 1977 an inventory of chemical

substances manufactured in the United States.

An initial inventory was published about 2-1/2

years late in June 1979 and updated in July 1980.

Information originally requested for the inventory was limited and EPA has proposed

rules requiring additional information for certain substances. In February 1980, rules requiring exposure information on approximately

2,300 substances were proposed (108). Additional information-gathering rules are scheduled

for proposal in 1981.

Section 8(c) of TSCA also requires manufacturers, processors, and distributors to notify

EPA of information which reasonably supports

the conclusion that a substance “presents a substantial risk” of injury to health or the environment. In addition, Section 8(c) requires the

maintenance of records indicating “significant

adverse reactions” alleged to have been caused

by a chemical substance. Allegation by employees are to be retained by industry for 30 years

and all other allegations for 5 years. These records are to be submitted to EPA upon request,

and EPA is investigating means of establishing

an automatic reporting system whenever a certain number of allegations are received in a 12-

month period for the same substance, process,

or discharge (109). Final rules to implement the

significant adverse reaction reporting requirement are expected in 1981.
Ch. 4—Methods for Detecting and ldentifying Carcinogens ● 149

Chemical Substances Information

Network (CSIN)

In February 1978, under mandate of TSCA,

EPA and CEQ established the Toxic Substances

Strategy Committee (TSSC) to facilitate interagency coordination of chemical information

collection, dissemination, and classification.

The Departments of Health and Human Services, Agriculture, Commerce, Defense, Energy,

Interior, State, and Transportation, and OSHA,

CPSC, and NSF participate in TSSC. IRLG and

the DHHS Committee to Coordinate Environmental and Related Programs are also members.

TSSC has formed a number of committees for

special tasks, and the data committee recommended the development of a broad-based network of data systems—CSIN. CSIN was

adopted by TSSC, and if sufficient resources

and personnel are committed, it should go a

long way toward the goal of providing convenient access to information about chemicals. Its

master file will contain all information collected

under TSCA; a subfile, stripped of confidential

data about trade secrets, will be available for

public use. CSIN will identify about 1 million

chemicals and for each one provide selected research and test data, references in the toxicologic and biomedical literature, and information about regulations that pertain to the

chemical (345). The system is still in the developmental stages, although some aspects were

expected to be operational in 1980 and the entire

system is to be completed within a decade.

CSIN will not be a single new system; rather

it will incorporate several systems already in

use. To facilitate locating information about a

single substance in more than one system, EPA

is developing an unambiguous identification

number system, which was another recommendation of TSSC’s data committee. In this way,

information about structure, chemical and

physical properties, production volume, uses,

application, distribution, and toxicity, now

stored in different systems, can be linked

together. Such systems do not necessarily contain information about human health effects,

but they can be used in combination with health

information systems.

Collection and Coordination of

Exposure and Health Data

Congress has responded to concern about the

collection and availability of data for assessing

environmental health risks. It has mandated

commissions and studies directed at improving

data collection, storage, and dissemination.

The Health Services Research, Health Statistics, and Medical Libraries Act of 1974, Public

Law 93-353, mandated the U.S. National Committee on Vital and Health Statistics to assist

and advise PHS with statistical problems bearing on health and the delivery of health services

which are of national interest. A committee recommendation was important to the establishment of the NDI.

The 95th Congress passed two acts which included sections pertaining to data collection for

assessing and reducing cancer risks. The Clean

Air Act Amendments of 1977 (Public Law

95-95) established the Task Force on Environmental Cancer and Heart and Lung Disease, to

focus efforts by EPA and various branches of

DHHS on issues relating to these diseases. The

task force is composed of representatives from

EPA, NCI, NHLBI, NIOSH, NIEHS, NCHS,

CDC, and FDA (340). The task force was directed to recommend, among other things (340):

. . . a comprehensive research program to determine and quantify the relationships between environmental pollution and human cancer . . .

[and] . . . recommend research and such other

measures as may be appropriate to prevent or

reduce the incidence of environmentally related

cancer . . . .

Initial efforts were focused on defining problems, categorizing relevant research programs,

and exchanging information among member

agencies and other appropriate groups. Activities related to prevention and reduction of environmental risks are planned to begin during

1981. ,

The task force established several project

groups to address specific areas of interest. Of

particular relevance to this assessment is the

Project Group on Exposure and Metabolic
150 . Technologies for Detemining Cancer Risks From the Environment

Mechanisms, established in May 1979. The

group is examining the interrelationship of exposure to a toxicant and body uptake, metabolism, and affected target organs. It is hoped that

this information will increase the ability of researchers to predict a chemical’s potential toxicity and establish which symptoms maybe associated with trace chemical levels in the body.

The Project Group on Standardization of

Measurements and Tests is primarily concerned

with obtaining reliable, comparable data on environmental and disease measurements. The

group has focused on “potential contributions to

the state of the art of environmental and occupational monitoring and testing that would

complement, rather than duplicate or overlap,

the efforts of individuals or agencies” (340).

They identified two problem areas common to

task force agencies:

1. There is a need for better resource allocation to optimize the quality of data since

agencies and laboratories charged with

monitoring activities typically have limited resources.

2. Researchers currently have limited means

of assessing the relationship and validity

of published environmental monitoring

data.

The Project Group on Standardization of Measurements and Tests expects to develop recommendations in these areas.

The Health Services Research, Health Statistics, and Health Care Technology Act of 1978

(Public Law 95-623) mandated the Secretary of

DHHS to initiate several efforts relating to the

impact of the environment on health. He is to

develop a plan for the collection and coordination of statistical and epidemiological data on

the effects of the environment on health and

prepare guidelines for the collection, compilation, analysis, publication, and distribution of

this information. The law also authorized the

Secretary of DHHS to “consult with and take into consideration any recommendations of the

Task Force” in developing the plan.

NCHS (252) recently published Environmental Health: A Plan for Collecting and Coordinating Statistical and Epidemiologic Data,

which reviews information currently available

from Federal data collection systems. A series of

recommendations are made to Congress for correcting gaps and deficiencies in environmental

health data systems. These recommendations

include the need for priority setting in new data

collection efforts, interagency coordination in

the environmental data collection process,

assurance of the quality of data, and linking

data on the environment and health.

NCHS (252) identified 64 ongoing systems in

18 agencies that gather environmental healthrelated data. At least two-thirds of these collect

either information on cancer incidence/mortality or data on cancer risk factors. Most of the

data collection systems identified are designed

to:

● collect health-related data,

● measure environmental pollutants and individual exposures,

● test specific interrelationships, or

● link data on the environment and health.

Linking systems that collect different kinds of

data appear to have the greatest utility for assessing associations of environment and health.

For example, the Upgrade system, which is concerned with water quality and health is a joint

effort of CEQ, EPA, NIOSH, and NCHS, and

integrates data from the Bureau of the Census,

mortality data from NCHS, and water quality

data from EPA and the U.S. Geological Survey.

OTA encountered an example of the oftenvoiced complaint that data are not in a form

easily accessible and useful to researchers. National mortality data were necessary to carry

out the analyses reported in chapter 2, but those

data were available in computer readable form

only for the years since 1968. OTA had to computerize the data back to 1933 to carry out the

analyses. The OTA computer tapes of cancer

mortality data will be made available to researchers. These data include deaths by age,

race, and sex for selected cancers, for each of the

years 1933 through 1978. All of the data on

these tapes are consistent with those available

on paper from NCHS.
Ch. 4—Methods for Determining and ldentifying Carcinogens 151

Not all informational systems release data for

public use and some that are released are of

limited usefulness. Data are often aggregated by

geographical regions (e.g., by county or State),

which precludes detailed analysis of exposures

on health. Individual identifiers are frequently

deleted because of privacy and confidentiality

constraints. This unfortunately hinders intensive specific epidemiologic investigations which

are facilitated by matching an individual’s exposures and lifestyle characteristics with health

status. Agencies with individually identified

records can sometimes conduct followup studies

to obtain additional information for investigation, e.g., NCHS recently initiated a followup

study, 10 years after the survey, of participants

in its HANES I survey, The followup will investigate current health status of participants as it

can be related to previously collected data.

Collection of useful epidemiologic information may be indirectly affected by the Paperwork Reduction Act of 1980, which passed during the last days of the 96th Congress. The act is

intended to improve use of existing data collection systems and to reduce the Federal paperwork burden placed on individuals, businesses

and governments by 25 percent within 3 years.

The act empowers the Director of OMB to review and approve Federal agency information

collection requests. Various medical and epidemiologic research groups, including NIH, expressed concern that Federal research into disease prevention could be impeded by the Paperwork Reduction Act and advocated the exemption of biomedical and epidemiologic research

(64), The Senate Committee on Governmental

Affairs decided against this exemption because

it determined that the act would not interfere

with disease prevention research.

In addition to reducing the paperwork burden, the act directs the sharing of information

among agencies to the extent authorized by law

and the establishment of a Federal Information

Locator System. This system will contain a description of all information collected by the Federal Government, and directions for obtaining

the information by all agencies and the public.

Successful implementation of this system should

enhance the quality of information available for

epidemiologic research.

Government Records and

Record Linkage

Government records contain a wealth of information about individuals that could be of

great value to researchers looking for associations between exposures and disease states. The

SSA, Internal Revenue Service (IRS), Veterans’

Administration (VA), the Bureau of the Census,

and NCHS are organizations with extensive

data collections. For the most part, details about

individuals are not readily available because of

legal and institutional barriers. Most critically,

it is difficult to obtain records of the same person from two or more sources. This can be a

major obstacle because one record rarely contains all desired information. For example, to do

a study relating mortality to occupational exposures, one could extract “occupation” from

the IRS record, “employer” and “industry” from

information collected by the SSA, and cause of

death from the death certificate filed in the State

in which the death occurred. The NDI, which is

described above, makes it easier to locate death

certificates.

Individuals in several Government agencies

have been promoting a Linked Administrative

Statistical Sample, a project designed to bring

together records of IRS, SSA, and NCHS (200).

The project planners aim to provide an improved data base for mortality research by compiling

statistical information from the participating

agencies on a sample of individuals. The starting point will be the l-percent CWHS (see

above). This effort has great importance as a

pilot for future projects to study cancer mortality, particularly contributions of occupational

exposures.

Records from different agencies have been

linked before on an ad hoc basis, e.g., VA has

cooperated in several studies (23), but the

broader scale now proposed has brought some

basic issues to the fore. The most fundamental

barrier to researchers acquiring data from more

than one file is that which is erected to preserve
privacy and confidentiality. Restrictions have

been tightened considerably in recent years by

the Privacy Act of 1974 and the 1976 amendments to the Internal Revenue Code. Although

epidemiologists have not been implicated, wellpublicized breaches of confidentiality and privacy have engendered suspicion among legislators and the public, about possible misuse of

easily accessible files. MacMahon (217) has

summarized the epidemiologist’s point of view:

To determine cancer risks among persons exposed to particular environmental factors, we

need to be able to link information relating to

the same individual at different times in his life

and to determine whether an individual exposed

in the past is now dead or alive and in what state

of health . . . . Maximum confidentiality means

minimum epidemiologic information and minimal effectiveness in identifying new cancer

hazards. In my opinion, we are well beyond the

point at which concern for confidentiality

seriously impairs the extraction of valuable

knowledge, even from routinely collected information. Working as an epidemiologist, one

comes to recognize the readiness with which

most people, patients or nonpatients, will supply even sensitive information if they believe the

cause is reasonable. Somehow, the issue of confidentiality becomes more difficult when it is

institutionalized or politicized. We must attempt

to convince the public’s representatives that a

reasonable balance can be achieved.

Other linkages, and the means to accomplish

them, have been suggested. One current proposal involves drawing a sample of several million individuals from those people who filled

out the 1980 long census form for future matchSUMMARY

Interest in cancer prevention and acceptance

of the idea that some substances cause cancer

have spurred developments in methods to determine which substances are associated with

cancer.

Epidemiology has played an important role in

identifying both carcinogenic substances and exposures which are associated with cancer although the causative agent may not be known.

ing to the NDI. This would facilitate matching

cause of death with personal characteristics

reported in the census. Another proposal has

been made to add cause of death information to

the SSA’s l-percent CWHS. However, since collection of cause of death data is not part of the

mission of SSA, it would presumably require

money from outside SSA for implementation.

The cited desirability of making records more

available for research purposes runs into conflicts with society’s intention of protecting the

individual’s privacy. The linking of individual

records between agencies would allow a person

with access to the system to obtain most or all

Government-held information about any individual. The potential for abuse is apparent. At

the same time, linkage, in the hands of a biomedical researcher, might quickly provide information about behaviors, exposures, and

health that could be obtained only with great

difficulty in any other system.

The Workgroup on Records and Privacy of

the Interagency Task Force on the Health Effects

of Ionizing Radiation (182a) has addressed the

problems arising from the conflict between access to records for research and the right to

privacy. It suggested changes in the Privacy

Act, the Tax Reform Act, and commented on

pending bills (in 1979) that would have permitted access to records under tightly controlled

conditions. The workgroup’s report is an excellent starting point for discussion of this complicated subject and provides possible directions

for, Federal efforts.

When available, epidemiologic data about cancer risks are the most convincing. At the same

time, identifying a carcinogen on the basis of

human disease and death means that other testing methods failed to identify the agent before

human illness resulted from it.

The most important laboratory method for

determining carcinogencit y is the long-term bioassay in laboratory animals, generally rats and
mice. The 1960’s saw marked increased interest

in the test, and NCI has played a major role in

designing appropriate test methods. NCI developed a large-scale bioassay program for testing,

evaluating, and documenting the carcinogenicity of environmental chemicals. It has also

supported the IARC program to review information on environmental carcinogens and publish findings in its authoritative monograph

series.

While the bioassay has been improved and is

widely accepted as an appropriate method to

identify carcinogens, it is expensive (each one

costs $400,000 to $1 million) and time-consuming (each takes from a minimum of more

than 2 years to a more realistic 5 years). Because

of those costs and limited long-term bioassay

capacity, other tests are being developed.

The short-term tests measure biological effects other than carcinogenicity (often mutagenicity) in bacteria, yeast, cultured mammalian

cells, or in intact lower organisms. Major international efforts have been completed and others

are ongoing to validate the ability of these tests

to identify correctly carcinogens and noncarcinogens. Some tests perform well in the validation experiments, and it is expected that they

will play an increasingly important role in identifying carcinogens.

Deciding to test a chemical in a short-term

test or a long-term bioassay involves studying

its structure. Some classes of chemicals are more

likely to be carcinogenic than others, some are

present in high concentrations in the environment, and some are viewed with suspicion for

one reason or another. Based on such information a chemical may be selected for testing. NTP

is developing a tier-testing scheme which first

assays a chemical in a number of short-term

tests. The chemicals that appear most risky as a

result of short-term tests will be accorded priority for further testing in long-term bioassays.

This NTP program promises to improve both

the use of information from short-term tests and

the usefulness of the bioassay program.

The establishment of NTP, which appears to

be moving toward an ordered, careful development of methods for testing and interpretation of results, and IRLG’s appearing as a single

voice for Federal regulatory procedures and

decisions promise further improvements. Additionally, IARC’s distinguishing between noncarcinogens and carcinogens and ordering

among carcinogens on the basis of test results is

an important step in increasing the usefulness of

the results.

Not included in testing systems, but discussed

here are already useful and potentially more

useful data collection systems. Several of these

systems were mandated by Congress to collect

information about exposures and health status.

Currently, inadequate resources and coordination may be hampering the performance of the

systems. Another major source of information,

the administrative data systems, were not developed as health information resources. However, both SSA and IRS collect some information which might be of great value for epidemiologic studies. Perhaps the most pressing need

in adapting the administrative data systems for

these uses is more consultation between epidemiologists and the data systems experts.
5

Extrapolation From

Study-Generated Data to

Estimates of Human Risk
Contents

Page

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............157

Numeric Extrapolation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........157

The Question of Thresholds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ...158

Numeric Extrapolation To Project Risk at Doses Below Those Tested . ......160

Quantitative Effects of Selecting a Model . . . . . . . . . . . . . . . . . . . . . ...........162

Virtually Safe Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............163

What Quantitative Projections Can Be Made From Negative Results . ..........164

Other Extrapolation Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........164

Extrapolation From Short-Term Tests to Human Risks. . . . ..................165

Carcinogenic Activity Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......166

Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........................166

The ED01 Experiment and Extrapolation Models . . . . . . . . . . . . . ..............167

Biologic Extrapolation From Animal Tests . . . . . . . . . . . . . . .................169

Comparing Measured Human Cancer Incidence and Mortality to Estimates

Made Using Extrapolation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... .170

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................172

LIST OF TABLES

Table No, Page

32. Expected Incidence of Tumors Calculated by Three Models When a Dose

of l.O Caused Tumors in 50 Percent of the Tested Animals. . . . . . . . . . .. ....163

33. Relative Human Risk Depending on How Dose Rate is Scaled From

Experimental Animals to Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....170

34. Comparison of Tumor Rates in Laboratory Tes tAnimals and Humans

Following Lifetime Exposures to Comparable Amounts of Each of Six Agents .171

LIST OF FIGURES

Figure No. Page

21.

22.

23.

24.

25.

26.

A Stylized Dose-Response Curve and Some Extrapolated Curves . .........158

Proportion of Mice With Liver Tumors v. Dose . . . . . . . . . . . . . ....,......167

Proportion of Mice With B1adder Tumors v. Dose . . . . . . . . . . . . .,........167

Proportion of Mice With Bladder Tumors v. Dose . . . . . . . . . . . ...........168

Proportion of Mice With Liver Tumors v. Dose . . . . . . . . . . . .............168

Proportion of Mice With Bladder Tumors v. Dose . . . . . . . . . . . . . . . . . . . . .. 168
5

Extrapolation From

Study-Generated Data to

Estimates of Human Risk

INTRODUCTION

Information about carcinogenicity is obtained

from exposing animals to measured doses of

suspect substances in the laboratory or by

studying associations between exposures to suspect carcinogens and development of cancer in

humans. In practice, both the animals and certain groups of humans, particularly those exposed in the workplace, are exposed to doses far

larger than those encountered by most citizens.

A number of “numeric extrapolation” methods

have been developed to estimate the effect of exposure to low doses based on observed effects at

high doses. When information about carcinogenicity is obtained from animals, “biologic extrapolation” techniques are employed to project

from animal results to estimates of human risk.

(In this report the word “hazard” is applied to a

substance or exposure that harbors a “risk” to

people who come in contact with it—i.e., a carcinogenic chemical is itself a hazard. Risk is the

probability of cancer developing as a result of a

particular exposure to the hazard. )

NUMERIC EXTRAPOLATION

This discussion describes information that

can be obtained from extrapolation, and comments on various extrapolation methods. It is

neither rigorous nor inclusive, and the interested (and mathematically sophisticated) reader

is referred to Heel et al. (170), Crump et al. (75)

and the Food Safety Council (FSC) (125) for

such treatments.

Toxicity testing produces data relating tumor

incidence (I) to dosage (D) as shown in figure

21. Generally, a smooth curve drawn between

In most cases, no adequate human data are

available for estimating risks, and it is necessary

to make both numeric and biologic extrapolation from measured responses in animals to estimate human risk. Less uncertainty attends making numeric extrapolations from observation of

human responses at high-exposure levels than

extrapolations from animal data. However,

such extrapolations are often complicated by

poor exposure data.

Extrapolation, like testing, is employed to

make regulatory decisions, and as in the case of

testing, a number of agencies have made statements about the methods they will employ.

These policy statements are necessary to explain, in the absence of agreed-on universal procedures, how the agencies intend to use bioassay

and epidemiologic data to estimate risk through

the use of extrapolation methods.

the experimental points, P1-P5, (solid line in

figure 21) is sigmoidal, or S-shaped. It can be

seen that the incidence of tumor formation decreases with decreasing dosage. The crux of the

extrapolation problem is what sort of line best

approximates the response in the region for

which data are not available. Or, what kind of

line should be drawn from point P1 to lower, unmeasured, response levels.

Graphic representations such as figure 21 do

not fully show the difficulties in estimating in157
——

158 ● Technologies for Determining Cancer Risks From the Environment

Figure 21 .—A Stylized Dose-Response Curve

and Some Extrapolated Curves

1/8 1/4 1/2 1 [) 2D 3D

D D D

Dose of test chemical

aExce ss tumor Incidence (perceni ) IS defined as:

tumors in exposed population – tumors in control population x 100

number of ex~osed population number of exposed population

— a sigmoid dose-response curve; infraltnear between O and P,

–-– linear extrapolation

——— supralinear extrapolation

------ line projected to a threshold

SOURCE: Office of Technology Assessment

cidence at very low doses. The first division on

the vertical incidence scale is 10 percent, which

means that 1 human or animal out of 10 developed cancer. For many agents, especially those

present in air or water, we are interested in

knowing what dose is projected to cause an incidence orders of magnitude less, e.g., 1 tumor in

100,000 animals or humans. Such small fractions cannot be seen on the figure, but they can

be calculated using any extrapolation method.

The solid curved line drawn from point PI to

the origin is a continuation of the curve constructed between the experimentally determined

points. It was drawn by eye, and it is representative of a number of smooth, concave upward

lines that can connect PI and the origin as a continuation of the sigmoidal curve constructed between P1 and P5

.

The Question of Thresholds

The solid line on figure 21 embodies the

premise that there is no threshold. A threshold

model would have the curve hit zero incidence

at some dose greater than zero, as is shown in

figure 21.

The threshold argument contends that there

are doses of carcinogens so low that they will

not cause cancer, and that no matter how many

animals are exposed to doses that low or lower,

no tumors will result. The counterargument is

that any dose of a carcinogen, no matter how

small, has a finite although small, chance of

causing a tumor, and, if an experiment were

performed with a sufficiently large number of

animals, such risk would be detectable.

The concept of a population threshold, which

is discussed here, includes the idea that there are

exposure levels below which no individual in

the population will develop cancer. No solution

to the threshold/no threshold argument can be

found by doing increasingly larger experiments

with more and more animals. If a given dose of

chemical causes no excess tumors in 1,000 animals, there is no guarantee that it will not cause

an excess when 2,000 are exposed.

Individuals may have thresholds, as suggested by the fact that all heavy cigarette

smokers do not develop lung cancer. Possible

biologic reasons advanced to explain such differences in susceptibilities include physiologic

and genetic variations among people. Another

reason for the apparent differences in susceptibility may be chance. Some heavy smokers

may be “luckier” than others in that their exposures do not trigger carcinogenesis, and they

may not develop cancer, or they may die from

some other cause before cancer develops. In any

case, it is as yet impossible to predict an individual’s threshold for even a single carcinogenic agent and impossible to derive a population’s threshold with current knowledge or

methods.

In a highly recommended article, Maugh

(224) reports on conversations with a number of

scientists and administrators from the National
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 159

Institutes of Health, private testing laboratories,

and industry. The conclusion of the article, apparently shared by the interviewed scientists

and administrators, is that resolution of the

threshold question is not now available:

. . . it is extremely unlikely that it would be

possible to distinguish between a linear doseresponse curve and a highly nonlinear one

(threshold), even in a large-scale experiment involving several thousand animals per dose level.

. . . statistical analysis of standard animal

carcinogenicity experiments, Schneiderman

[then-Associate Director of the National Cancer

Institute (NCI)] concludes, does not now, and

probably never will, resolve the threshold question, There are, he says, simply too many “biologically reasonable” mathematical models,

both implying and denying the existence of

thresholds, that will fit the observed results.

. . . there is so little data and so many interpretations, Gehring [Dow Chemical Co. ] says,

arguing about thresholds is an exercise in futility.

The view that thresholds cannot be demonstrated is accepted in publications of the National Research Council (NRC) (262), Interagency Regulatory Liaison Group (IRLG) (180), FSC

(125), and, for tumors resulting from somatic

mutations, by the American Industrial Health

Council (AIHC) (8). Despite the apparent agreement that it is impossible to demonstrate a

threshold, many individuals object to the idea

that thresholds should not be considered in

making decisions about carcinogens.

In particular, some tumors are thought to result from irritation or mechanical injury, and

threshold models are postulated for those. An

often mentioned example is Clayson’s (60) finding that bladder stones are found in conjunction

with some bladder tumors. Stone formation

may be dependent on intake of large quantities

of a chemical; if exposure to the chemical is sufficiently low so that no stones are formed and if

stone formation is necessary for carcinogenicity, then a threshold should exist. This and

other examples of “epigenetic” tumors can be

considered separately from tumors that originate from somatic mutations. Just as thresholds

for acute toxic responses differ, thresholds for

stone formation most likely differ among individual animals. Therefore, it may be impossible

to determine exactly what dose is necessary to

produce a stone and therefore pave the way to a

tumor. Nevertheless, if the threshold for stone

formation in animals is found to be 100 or 1,000

times greater than human exposure levels, the

observation takes on great significance. If stone

formation is a necessary precursor to tumor appearance, and no stone formation occurs at human exposure levels, it becomes difficult to

maintain the position that human exposure levels present a carcinogenic risk. The difficulties in

this argument are the possibility that some humans may produce stones at very much lower

doses than animals and that carcinogenicity

might not proceed through stone formation in

humans. Such caveats seem reasonable to some

people; unreasonable to others. Experimentation and more sophisticated models may eventually settle such questions. However, for the

present, positions on these issues reflect organizational policy and individual judgment.

Gehring, Watanabe, and Young (139) describe differences between metabolism of chemicals administered at low and high doses. Measurement of these differences is called pharmacokinetics. In general, biochemical mechanisms

to detoxify chemicals and to repair damage to

DNA are seen as having a better chance of detoxifying and repairing damage at low doses

than at high doses. High doses can swamp defense mechanisms resulting in toxic effects;

lower doses are seen as presenting little or no

risk.

Metabolic differences measured by pharmacokinetics might have important effects on the

shape of the dose-response curve. If a metabolize

of an ingested substance is the actual carcinogen, and the production of the metabolize increases out of proportion to dose above a certain level, then the dose-response curve might

bend upward at that point. Pharmacokinetic

data are not always collected, and the standard

bioassay which produces data at only two dose

levels does not provide sufficient information to

see if differences in metabolism might be important in the slope of the dose-response curve.
160 ● Technologies for Determining Cancer Risks From the Environment

Biochemistry of a particular compound may

be affected by other compounds present in the

organism. Cancer is a relatively common disease, and if avoiding cancer involves biochemical detoxification processes, it may be that

small doses of many substances can swamp the

process as well as large doses of a single substance. If this is correct, the addition of the carcinogens, even at low doses, might be enough to

overcome the detoxification mechanism.

Cornfield (67) described quantitative extrapolation models to take into account differences

in metabolism at high and low doses. His paper

was criticized because it postulated a threshold

(see 36,73,229,276,.319), and his hope that the

paper would lead to discussion of the merit of

his models apparently was not realized (68). The

difficulty with models which propose detoxification activities for producing thresholds is

that the detoxification has to be instantaneous

and complete. Otherwise molecules might

escape detoxification and initiate a carcinogenic

event.

Donald Kennedy, a few months after leaving

the post of Commissioner of the Food and Drug

Administration (FDA), expressed his opinion

that thresholds may exist for some chemicals:

Dr. Kennedy said that the [Delaney] clause in

the FDA’s authorizing legislation codifies the hypothesis that there is no threshold concentration

below which a chemical does not cause cancer.

And although this hypothesis “probably holds

most of the time, ” Dr. Kennedy said that he was

“as certain as I can be of any scientific prediction

that some day, very soon, some compound will

be demonstrated to have a threshold level for

cancer causation” . . . (274).

It is difficult, if not impossible, to marshal

more evidence on one side of the threshold question than on the other. The ascendancy of the

more conservative view, that thresholds cannot

be identified for human populations, can be

taken as a policy decision made in the interest of

protecting the public health. Such a general policy can not exclude the possibility that a threshold may someday be demonstrated.

Numeric Extrapolation To Project Risk

at Doses Below Those Tested

The shape of the line in figure 21 depends on

the number of tumors observed at points P1

-P5.

No matter what method is used to extend the

line below P1

, that extension represents an estimate. Any number of smooth curves can be

drawn from point P1 to the origin; for convenience, the possible lines will be divided into three

families: supralinear, linear, and infralinear. A

detailed discussion of these models as they relate

to radiation and cancer is available in a paper

by Sinclair (329).

Supralinear Extrapolation

A supralinear extrapolation is presented on

figure 21. It says that some doses less than ID

are relatively more effective in inducing tumors

than doses equal to ID. Conceptually the contention that lower doses are more carcinogenic

is easy to address. Further tests at lower doses

would resolve the question, but additional tests

are costly and time consuming.

Supralinear models are considered for two

reasons. In several NCI bioassays, the tumor

yield was lower at the high dose than at the low

dose (102). In other words, the lower dose was

more efficient at producing tumors. The explanation is that the higher dose was so toxic

that it killed animals before they developed

tumors. The other reason for considering supralinear responses is that some studies of

radiation-induced cancer have been interpreted

as producing supralinear dose-response curves

(e.g., 241), but those interpretations are hotly

disputed.

Such responses might result from the presence

of a subpopulation of more sensitive individuals. On figure 21, the supralinear response between the origin and P1 represents the tumors

induced in the proposed sensitive fraction of the

population; the solid line drawn from the origin

to P5 represents the sensitivity of the remaining

members of the population. The difference between the two lines between the origin and P1
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 161

represents the contribution of the sensitive subpopulation to the total response at doses below

ID. It can be seen that the sensitive subpopulation accounts for the majority of tumors that

occur below P1

. Clearly, if this model describes

risks, reducing doses to 1/2D or l/4 D would not

significantly reduce tumor incidence, and a

supralinear dose-response curve would force

lowering doses to very small fractions of D to

significantly reduce tumor incidence.

Nonartifactual, supralinear dose responses

have rarely been observed in bioassays but

neither would they be expected. Laboratory

animals are highly inbred and each animal

should be more nearly equally sensitive than are

members of human populations. Supralinear

response models have been advanced but do not

now receive the acceptance accorded to the

other two general models.

Linear Extrapolation

A linear model is shown by the straight line

that extends from P1 to the origin on figure 21. If

the true dose-response curve is represented by

the solid curved line from P1 to the origin, then

the linear model is “conservative” and overestimates the number of tumors at all doses between P1 and the origin.

The paper by Crump et al. (75) is an oftencited and important argument for linear dose responses at low doses. The paper points out that

25 percent of the U.S. population will develop

cancer as a result of existing carcinogenic influences (see ch.3). Crump et al. (75) propose

that any new carcinogenic substance interacts

additively with exposures and behaviors already present in the environment. Their mathematical theories predict that regardless of the

shape of the dose-response curve at high exposures, at low doses cancer incidence should be

proportional (linear) with exposure to the substance under study.

Gaylor and Kodell (137) argue that no risk

estimate can be very reliable for doses below

that associated with the lowest data point (Pl in

figure 21) because there is no information available below point P1

. They propose the use of

“linear interpolation” and the 95-percent upper

confidence level to estimate the maximum risk

posed by a substance.

Error is associated with any experimental determination, and standard methods can be used

to calculate “confidence limits” for each estimate. Usually “95-percent confidence limits”

are calculated for carcinogenicity experiments;

they are plotted as vertical bars extending from

the data points, as shown on the figure. The 95-

percent confidence limit says that given the experimentally determined incidence and the size

of the experiment, we can be 95-percent certain

that the actual incidence represented by the

point estimate lies inside the error limits.

In the method of Gaylor and KodelI (137) a

line is drawn from the upper limit of the error

bar on the lowest data point to the origin. Inspection of figure 21 shows that this method

projects a larger risk than does linear interpolation from the point P1 to the origin. This is

not an estimate of risk; it is an estimate of the

upper bound of risk.

Objections to including upper confidence

levels in extrapolation are frequently voiced.

The practice of including them is seen as introducing a “safety factor. ” Industry spokesmen

(9a) and others contend that the best risk estimate should be made and the safety factors

added after the estimate is made.

As a practical matter, there is often no alternative to the linear model. The dose-response

curve in figure 21 is an outrageous overstatement of the data that are generally available.

Bioassays carried out according to NCI’s cancer

testing guidelines (331) produce only two data

points. The Environmental Protection Agency’s

(EPA) (102) analysis of many such tests showed

that tumor incidence was sometimes higher and

sometimes only measurable at the lower of the

two doses because other toxic effects killed

animals at the higher dose. Left with only the

response at the lower dose, there is little choice

available but to estimate responses at still lower

doses on the basis of simple proportionality.

Such calculations produce a straight line from

the experimental point to the origin.

IRLG (180) did not discuss how to extrapolate

when more than one data point is available; it
162 . Technologies for Determining Cancer Risks From the Environment

recommends linear extrapolation (proportionality) for making estimates from a single point.

IRLG further proposes that the upper confidence

level be used as the starting point for extrapolation to achieve “an added degree of protection . . . .“

A linear extrapolation model from the lowest

positive data point to zero dose (104) was used

by EPA’s Carcinogen Assessment Group (CAG)

until the summer of 1980. At that time, CAG

(48) announced it was going to discontinue use

of the linear model and subsequently employ a

model developed by Crump. The CAG decision

was not made because evidence had shown the

linear model was poorer than the new one (48):

There is no really solid scientific basis for any

mathematical extrapolation model which relates

carcinogen exposure to cancer risks at the extremely low level of concentration that must be

dealt with in evaluating the environmental hazards.

The now-adopted model is linear at low

doses, and, in practice, produces estimates of

risk at low doses which “ . . . are not markedly

different from those obtained with the former

procedure based on the one-hit [linear] model”

(230). However, the new model does allow consideration of data produced above the linear

part of the curve (points P4 and P5 on figure 21)

to influence the slope of the line and the range of

error associated with each point.

Infralinear Extrapolation

The curved line between P1 and the origin on

figure 21 or any curved line which remains below the straight line is infralinear. Such models

predict lower tumor incidence than the linear

model. If it were decided that a certain level of

risk were acceptable, higher exposure to the

chemical would be allowable under infralinear

than under linear models.

A number of such models have been developed and are well described in FSC’s (125) report. All of them produce concave upward lines

between the origin and the lowest data point

(Pl

, in figure 21). Different models produce differently shaped lines. It is suggested (e.g., 125)

that the model which produces the line that best

fits the data points (Pl to P5 in figure 21) is the

model to use to predict risk between P1 and the

origin. Unfortunately, usually any of the models seems to fit the available data points about

equally well (9a,125,138,180). The reasons for

the equally good fits are that generally only one,

two, or three data points are available and all of

them measure incidence above 10 percent. Data

points at such relatively high response rates do

not often provide enough information to decide

what the dose-response curve is at an incidence

of 1 percent or less.

QUANTITATIVE EFFECTS OF SELECTING A MODEL

Selection of the appropriate model for estimating risks at low doses would be made easier

if some models clearly did not fit the observed

data points. As mentioned above, hardly ever is

it possible to select the best model or even to reject the worst on the basis of fit to observed data

points. The low end of the dose-response curve

is most informative for selecting the correct

model but it is the part that is most difficult to

measure. In practice, incidence rates in animal

tests much below 113 percent (5 tumor-bearing

animals in a test population of 50) can seldom

be distinguished from the rate of spontaneous

tumors.

Table 32, derived from a paper by Brown

(35), shows that two infralinear models and the

one-hit model, which is essentially linear at

doses that cause an incidence of 10 percent or

less, are indistinguishable at high doses. For the

table, a dose level of one was set as sufficient to

cause an incidence of 50 percent. The expected

incidence using higher doses or doses as low as

one-sixteenth are nearly equal regardless of the
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 163

Table 32.—Expected Incidence of Tumors Calculated by Three Models When a

Dose of 1.0 Caused Tumors in 50 Percent of the Tested Animals

Projected percentage of tumor bearing animals

Single-hit model

Log-normal model Log-logistic model (linear at incidence

Dose level (Infralinear) (Infralinear) below 10°/0)

16 98 96 100

4 84 84 94

1 50 50 50

1/4 16 16 16

1/16 2 4 4

1/100 0.05 0.4 0.7

1/1 ,000 0.00035 0.026 0.07

1/10.000 0.0000001 0.0016 0.007

SOURCE: Adapted from Brown (35).

model. Brown (35) points out that no experiment of practical size could distinguish among

the three models at those dose levels.

However, at much lower dose levels of 1/100,

1/1,000, and 1/10,000, the models diverge

greatly in their projections of incidence. These

greatly lower dose and response levels are often

the ones of most interest for estimating human

risks, but they cannot be measured. The incidence measured at higher doses do not provide

sufficient information to choose the appropriate

model, These problems plague all extrapolation

efforts.

In general, either a linear or infralinear model

is used for extrapolation. The linear model predicts a higher incidence at low doses than does

the infralinear model.

Selection of the correct extrapolation model is

important for only one of the three possible regulatory strategies for carcinogens. The first

strategy is to accept either human or animal evidence as sufficient to identify carcinogens, and

once the identification is made, try to eliminate

the exposure. This approach requires no quantitative or numeric extrapolation. The second

approach uses biologic and numeric extrapolation to rank substances in order from that expected to be most carcinogenic to those that are

noncarcinogenic. This relative ranking can be

accomplished by consistently applying any

model, and the numerical accuracy of the

estimated incidence is not critical. The third approach, which includes a quantitative estimate

of human risk to be used in risk-benefit computations or to consider levels of acceptable risk

requires the most accurate numerical estimate.

Clearly, in this case, the selection of models is

important because the numbers produced by

different models vary across a wide range,

Virtually Safe Doses

A very low risk of cancer, say, one chance in

million lifetimes, is sometimes suggested as a

virtually safe dose. Any extrapolation model

can be used to calculate the dose which will produce such a risk, and different models produce

very different estimates for the virtually safe

dose (see table 32 and 125,170). As shown on

figure 21, infralinear models predict higher virtually safe doses (i.e., lower risks at any dose)

than does the linear model.
164 ● Technologies for Determining Cancer Risks From the Environment

WHAT QUANTITATIVE PROJECTIONS CAN BE MADE

FROM NEGATIVE RESULTS (ZERO

IN A TEST POPULATION)?

No tumors occurring in a test population of

100 animals or no excess tumors among 100 animals as compared with the number of tumors in

100 control animals does not show that zero

cancer risk is associated with the chemical. Instead standard statistical calculations based on

zero excess tumors in 100 animals show that we

can be 95-percent confident that the actual incidence of tumors is no more than 4.5 percent.

This estimate of the incidence of tumors that

might have gone undetected is called the upper

confidence limit. The percentage can be reduced

by testing more animals, for instance, finding

zero excess tumors in 1,000 animals would mean

that we can be 95-percent confident that the actual incidence is no more than 0.45 percent.

Proceeding with the illustration of zero excess

tumors in 100 animals, assume that the dose administered to the animals was 1,000 times higher

than that to which humans are exposed. Linear

The supralinear, linear, and infralinear models are all dichotomous. They compare the number of tumors or tumor-bearing animals in the

exposed population to the number in the controls. In both populations, the analysis depends

on the presence or absence of tumors. Other

models can be used to make inferences about the

times (or ages) at which animals develop tumors

in response to exposures.

Two of these models have been used extensively to describe animal and human “time-totumor” data. The lognormal model described in

Chand and Hoe] (57), predicts that the average

time-to-tumor is longer at low doses. An important outcome of this model is that at sufficiently

low doses, the time necessary for tumor development may exceed the expected lifespan. Such

a long latent period would produce a “practical

threshold.” The Weibull model (also described

EXCESS TUMORS

extrapolation (proportionality)

posure of the U.S. population

predicts that exto that chemical

at 1/1,000 the level fed to) the animals will result

in fewer than 10,000 cases of cancer assuming

equal sensitivity between man and animals. The

estimated risk would be reduced if the experiment on which it is based is more sensitive. For

instance, finding zero excess tumors in 1,000

animals (instead of 100) would reduce the estimated risk to fewer than 1,000 cases.

The statistics of the above exercise are not

questioned, but they are seldom applied.

Although a test cannot show that a substance

presents no risk, much less concern is attached

to substances that cause no excess of tumors.

The risk associated with substances that are

negative in bioassays is qualitatively lower, and

the consideration of quantitative risk estimates

from negative experiments is of minor importance.

OTHER EXTRAPOLATION MODELS

in 57) predicts that the average time-to-tumor is

nearly independent of dose. This prediction

means that an increase in dose simply causes

more cancers; it does not shift the age distribution at which they occur. The assumptions and

predictions of these two models are quite different. Unfortunately both are apt to give adequate fits to any available data set, making it

difficult to reject one in favor of the other. IRLG

(181) concluded that these models have not received the attention that has been focused on dichotomous dose- incidence relation models, and

it recommends more research be directed toward exploring them. The mathematics for

these models is sophisticated, and the interested

reader is referred to Chand and Heel (57).

At this time, discussion of other models is

more an academic than a policy exercise. Opposing camps are for or against quantitative ex-
Ch. 5—Extrapolation From Study-Generated Data to Estimates of Human Risk ● 165

trapolation, and among those favoring it, the cl). There is no agreement about another single

argument is between those for and against using model being offered as an alternative at this

linear extrapolation (including EPA’s new mod- time.

EXTRAPOLATION FROM SHORT-TERM TESTS TO HUMAN RISKS

McCann et al. (227) and McCann and Ames

(226) showed that about 90 percent of the carcinogens tested in the Ames test were mutagenic

(see ch. 4). Meselson and Russell (235) developed a model to compare the mutagenic and

carcinogenic potency of tested chemicals. Fourteen chemicals were analyzed because there

were sufficient mutagenic and carcinogenic data

available to construct dose-response curves for

each. The correlation between animal carcinogenicity and bacterial mutagenicity was excellent for 10 of the 14 compounds. The other

four compounds (all nitroso-compounds) were

more potent as carcinogens than as mutagens.

A spirited exchange of views resulted from

the suggestion that quantitative relationships

exist between mutagenicity in the Ames test and

carcinogenicity in animal tests. Ashby and

Styles (18) challenged the idea that such relationships were common, and Ames and Hooper

(12) responded that they were.

The International Program for the Evaluation

of Short-Term Tests for Carcinogenicity (188)

distributed 42 chemicals to each of 12 laboratories for testing in the Ames system: To

eliminate bias, none of the laboratories knew

the identity of the chemicals. There was excellent agreement among test results obtained in

different laboratories and about 80 percent of

the carcinogens were scored as mutagens and

about 80 percent of the noncarcinogens were

scored as nonmutagens. These numbers compare well with those in the literature that describe results from experiments in which the investigators knew before the mutagenicity test

was run that the chemicals were or were not carcinogenic. Although the 80-percent is lower

than the 90-percent accuracy sometimes reported, the program included a number of

chemicals that are known to present difficulties

for the Ames test. In a qualitative sense, the test

performed very well, but mutagenic potency did

not correlate with carcinogenic potency. In

other words, the results from this program do

not support the idea that there is a quantitative

relationship between Ames test results and carcinogenicity in animals. Similar results showing

good qualitative and poor quantitative agreements between mutagenicity and carcinogenicity were reported by Bartsch et al. (22).

Meselson and Russell (235) reported that sufficient quantitative data were available for two

human carcinogens, aflatoxin B and cigarette

smoke, to allow comparison of mutagenic potency to carcinogenic potency in humans. Correlation between carcinogenicity in humans and

mutagenicity was good for the two compounds,

and the Meselson and Russell paper raised the

possibility that human cancer risks might be

predicted from mutagenicity data. Acceptance

of such a procedure is far away and will depend

on much more data being available to support

the proposed quantitative relationships.

Clearly, controversies now exist about the

value of extrapolations made from short-term

tests. It seems reasonable that, as use of shortterm tests increases, such projections are going

to be made, but some initial optimism about the

value of quantitative extrapolation from shortterm tests to carcinogenicity is apparently

fading.
166 . Technologies for Determining Cancer Risks From the Environment

CARCINOGENIC ACTIVITY INDICATORS

The NRC Pesticide Committee (267) recommends calculating potency expressions, “Carcinogenic Activity Indicators” (CAI), for tested

chemicals. For each point of a dose response

curve (fig. 21), the number of chemical molecules ingested divided by the animal body

weight can be related to the excess percentage of

tumor-bearing animals in the exposed population.

excess percentage of

subjects in which tumors tumor

CAI = are observed = incidence

lifetime dose dose

(molecules/kg of

body weight)

CAIs do not have to be based on total tumors,

for instance, site specific tumors may be

counted, the analysis may be limited to one sex,

only malignant tumors may be counted, or

other alterations can be made as wanted. In

practice, the number of molecules of different

substances, S1, S2, and S3 required to induce

the same percentage of excess tumors can be

compared to determine which is the most potent

carcinogen. CAIs will probably be different for

each point on a dose--response curve because the

POTENCY

Ames et al. (14) have analyzed more than

l,500 bioassays carried out on some 600 chemicals. For each experiment, they have calculated

a potency index, TD50, which is calculated as the

total dose of substance necessary to produce

tumors in 50 percent of the animals. They expect to compare potency:

1.

2.

3.

4.

5.

among multiple tests run on the same substance in the same strain and species;

between male and female animals;

between different strains of the same animal;

between different sites in different animals; and

between rodent tests and 26 tests that have

been carried out: in monkeys.

points seldom fall in a straight line, but comparisons can be made at comparable doses.

Using information about exposure levels for

human populations, the number of molecules

that compare to human exposures can be calculated. Linear extrapolation is then to be used to

estimate the animal response at human exposure

level. This method is especially appropriate for

comparing chemicals with similar uses, and if

applied, would assure that the most and least

risky ones based on animal data are identified.

The procedure does not make predictions of

human cancer risks from animal data and

avoids the problems associated with biologic extrapolation. The NRC committee (267) urges

that only epidemiologic data be used to estimate

human risk; it restricts the use of animal data to

making comparisons of carcinogenicity in animals. (Such an approach is especially attractive

when deciding about regulating pesticides. Substitutes are often available and CAIs offer a

method to decide on the less or least risky one.

This suggestion corresponds to the second possible use of extrapolation discussed in Quantitative Effects of Selecting a Model above. )

The results of this massive project is expected to

provide much information about biologic extrapolation from species to species and about

potencies.

Ames et al. (14) mention that preliminary

results show that there is usually less than a tenfold variation in potencies among rodents. This

level of agreement was also found by Crouch

and Wilson (72) for most of 70 chemicals tested

in both rats and mice by NCI. Crouch and Wilson included tumors which were not present at

“statistically significant” levels in their analyses.

Therefore, some chemicals judged positive in

only one species by NCI (146) have potencies

that agree within a factor of 10 between rats and

mice although one is statistically significant and
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 167

the other is not. Results showing a substance is fers from species to species. This information

much more potent in one species than in another will also be important in efforts to improve exwill suggest that metabolism of the chemical dif - trapolation methods.

THE

The

search,

known

EDO1 EXPERIMENT AND EXTRAPOLATION MODELS

National Center for Toxicological Rea joint FDA/EPA laboratory, tested the

bladder and liver carcinogen 2-acetylaminofluorene (2-AAF) in approximately

24,000 female mice. This experiment was designed to study dose responses down to a 1-

percent tumor incidence, i.e., the effective dose

for a l-percent (0.01) response (ED01).

Figures 22 and 23 show the results of postmortem examination for liver and bladder tumors in animals exposed to 2-AAF for between

21.5 and 28.5 months. The curve that describes

the liver tumors (fig. 22) shows no threshold

and

The

(fig.

dose

increases almost proportionally to dose.

curve that describes the bladder tumors

23) gives an impression of a “threshold”

below 60 ppm of 2-AAF. Gaylor (136)

Figure 22.—Proportion (P) of Mice With

Liver Tumors v. Dose (21.5 to 28.5 months)

0.80

0.60

P

0.40

0.20 .

.-.

4 0 80 120 160

2-AAF (ppm)

SOURCE Llttlefleld, et al (213)

Figure 23.— Proportion (P) of Mice With Bladder

Tumors v. Dose (21.5 to 28.5 months)

0.80

0.60

P

0.40

D

0.20 -

I

40 80 120 160

2-AAF (ppm)

SOURCE Llttlefleld, et al (213).

ascribes the apparent threshold to a lack of

resolution of the graph for low tumor rates. He

replotted these same data on an enlarged scale

(figure 24) to show that the number of bladder

tumors increases with dose even at lower doses.

This diagram supports the idea that there was

no threshold. However, there is a dramatic

change in slope of the line between 60 and 75

ppm, and the efficiency of 2-AAF in causing

tumors increases greatly at doses above 60 ppm

(fig. 24).

Carlborg (50) has also analyzed the data from

ED01. He does not argue that the bladder cancer

data show a threshold, but he does contend that

neither the bladder nor the liver data fit a onehit (linear) model. In addition to trying to fit a

one-hit model to the data, he also tried the
—

168 ● Technologies for Determining Cancer Risks From the Environment

Figure 24.— Proportion (P) of Mice With Bladder

.008

.006

P

.004

I

.002

0

Tumors v. Dose (21.5 to 28.5 months)

20 40 60 70 75 a

2-AAF (ppm)

NOTE: The vertical scale has been expanded 100 times compared to figure 23

— line fitted to data points between () and 60 ppm

-—- slope of line between 60 and 75 ppm (derived from figure 23)

SOURCE: Gaylor (136) and Office cf Technology Assessment.

Weibull model, a “generalization of the one-hit

model. ” Figures 25 and 26 represent his analysis

of the two sets of data, and the “best-fitting onehit and Weibull models” are plotted in both

figures. It can be seen that the Weibull model

provides a better fit, especially with the bladder

tumor data. Carlborg (50) also states that the

one-hit model fits well with only the three

lowest dose points from the liver tumor data.

The Weibull model produces a different slope

for the line to be drawn from 30 to O ppm. Carlborg calculates that a 0.000045 ppm dose of 2-

AAF is necessary to produce a one in a million

risk of liver cancer using the one-hit model.

Using the Weibull model, the calculated dose for

a one in a million risk is 100 times higher,

0.0045 ppm. In other words, use of the Weibull

model would allow exposures 100 times higher

than the linear model if there were agreement

that a one in a million risk were acceptable.

Despite the large number of data points from

ED01, Gaylor (136) argues that a “best” model

Figure 25.—Proportion (P) of Mice With

Liver Tumors v. Dose (24 months)

.50 -

w

Welbull

.40 -

P

.30 -

.20 -

.10 -

.

0 20 40 60 80 100 120 140 160

2-AAF (ppm)

SOURCE: Carlborg (50)

Figure 26.— Proportion (P) of Mice With

Bladder Tumors v. Dose (24 months)

1.0 ‘ 4

.80 -

.60 -

d

P Wdbuli /

.40 -“ ., /

.20 “

,,

-+

+ 1 I

o 20 40 60 80 100 120 140 160

2-AAF (ppm)

SOURCE: Carlborg (50)

cannot be chosen on the basis of fit with the data

and that the Weibull model cannot be singled

out above all others. Furthermore, he says that

several models fit the observed data about

equally well, and that they predict very different

levels of risk at doses between O and 30 ppm 2-

AAF (see discussion of different models in

35,49,51,123,170).
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 169

Obviously, animal data can be best used

quantitatively to estimate potential risks within

the same animal species under test conditions.

These estimates cannot be used directly to estimate human risks. Other “biologic” assumptions are necessary to extrapolate from animal

data to estimates of human risk.

BIOLOGIC EXTRAPOLATION FROM ANIMAL TESTS

Bioassay guidelines call for testing in two

species. Qualitative judgments are based on

whether a tested substance causes tumors in

both, only one, or neither species. Sometimes, a

substance is reported positive (causes tumors) in

only one species and negative in another. The

frequency with which this problem is encountered can be estimated from Griesemer and

Cueto’s (146) discussion of the results of the NCI

bioassay program (see app. A). Of the 98 chemicals for which “very strong” or “sufficient”

evidence of carcinogenicity was found in either

rats, mice, or both, 54 were positive in only one

species. An analysis of test results from 250

substances (300) found 38 percent were carcinogenic in neither rats nor mice, 15 percent were

carcinogenic in either the rat or the mouse but

not both, and 44 percent were carcinogenic in

both. Crouch and Wilson (72) and Ames et al.

(14) tend to dismiss these discordant results between rats and mice because tests analyzed by

their methods, which consider experimental

error and test sensitivity, are in agreement much

more often.

In cases in which there are apparent species

differences in sensitivity, the positive result is

generally accepted as more important. The Office of Science and Technology Policy (281),

IRLG (180), the Occupational Safety and Health

Administration (279), and American Federation

of Labor/Congress of Industrial Organizations

(7) all present arguments for following this

course. AIHC (8) and Purchase (300) present

arguments against deciding that the more sensitive animal is predictive for human response.

The disagreement continues, but in Federal programs, extrapolation is based on results from

the more sensitive species.

Accepting that experimental animals provide

appropriate data for extrapolation to estimates

of human risk, a decision has to be made about

how to adjust the dose measured in the bioassay

to the dose experienced by humans. A mouse or

rat, of course, is much smaller than a human,

and the dose necessary to cause a carcinogenic

response is less than that required in humans.

Three “scaling factors” are in general use to

make allowance for the different sizes and rates

of metabolism between experimental animals

and humans. The three are listed below in order

from least conservative, that is the one that

predicts the lowest human risk, to the most conservative. The fourth scaling factor is less often

used, but it is included because it was used for

the estimates reported in table 34. For rats and

mice, the most commonly used laboratory animals, the relationship between scaling factors

and estimated risk in man for the same doses are

shown in table 33.

1.

2.

3.

Exposures may be adjusted on the basis of

relative body weights, milligram of agent/

kilogram of body weight/day (mg/kg/

day), for animals and humans. This method is most generally used by toxicologists.

In cases where the experimental dose is

measured as parts per million in food, air,

or water and human exposure is through

ingestion, the dose of the chemical is expressed as parts per million. This method

is generally used by FDA and in some

cases by EPA.

Exposure may be adjusted on the basis of

the relative surface areas of the test animal

and humans: milligram of agent/surface

area/day, for animals and humans. It is

generally expressed as milligram of substance/square meter of surface area/day

or mg/m2

/day. EPA uses this scaling factor.

BII-4 31 9 - 81 - 12
170 ● Technologies for Determining Cancer Risks From the Environment

Table 33.—Relative Human Risk Depending on How Dose Rate is Scaled From

Experimental Animals to Humans

Risk projected for humans when an identical dose is

scaled by different factors

Milligram Parts per million Milligram Milligram

Kilogram Kilogram

Experimental animal body weight/day In diet m

2 body area body weight/lifetime

Mouse 1 6 14 40

Rat 1 3 6 35

SOURCE: Off Ice of Technology Assessment.

4. Exposures may be adjusted on the basis of

relative body weight over lifetime, milligrams of agent /kilogram of body weight/

lifetime (mg/kg/lifetime).

As can be seen from table 33, the choice of

scaling factor can make a difference of up to

fortyfold in estimating human risks. The mg/

kg/day scaling factor was arbitrarily set equal to

1.0. Use of the mg/m2/day factor (for instance)

projects that humans would have 14 times the

risk of a mouse for equivalent doses measured in

mg/kg/day. The information given in table 33

allows a comparison to be made among the scaling factors. However, it is important to remember that great uncertainties surround biologic

extrapolation because of possible differences between laboratory animals and man, and no

great assurance is attached to any number in

table 33.

COMPARING MEASURED HUMAN CANCER INCIDENCE AND

MORTALITY TO ESTIMATES MADE USING EXTRAPOLATION

The more troubling and more fundamental

problem with biologic extrapolation concerns

questions about how closely the test animal

resembles humans. This problem is partially related to differences in the greater genetic complexity of human populations. Populations of

test animals are highly inbred and are almost genetically identical. Populations of humans are

outbred and include greatly differing genotypes.

There is no way to deal with the problem of

humans that may differ in sensitivities because

there is seldom, if ever, a way to associate sensitivities with individuals. The other problem

concerns differences in metabolism between test

animals and humans. Few are well understood,

and many may be unidentified.

Laying these problems aside, a few efforts

have been made to compare human cancer incidence or mortality to the levels of incidence or

mortality extrapolated from animal studies. The

number of such attempts is limited by the few

cases for which data are available both from experimental animals and from humans. The Consultative Panel on Health Hazards of Chemical

Pesticides of the National Research Council’s

Study of Pest Control (262), identified six

chemicals for which such comparisons could be

made. Comparisons were made on the basis of

lifetime dosage (expressed as milligram chemical/kilogram body weight/lifetime) in animals

and in humans. Table 34 shows those findings.

It can be seen that for three chemicals the incidence of human tumors was essentially that

predicted from animal studies, and for the other

three, extrapolation from animal data overestimated human risk as measured by epidemiology. Crouch and Wilson (72) have made

similar comparisons for 13 chemicals (including

the 6 in table 34). They reported good agreement between predicted and observed human

tumors rates, using a linear nonthreshold extrapolation model. Crouch and Wilson (72) also

calculated “scaling factors” from their experiments and concluded that humans are twice as

sensitive as mice and between one-third and

three times as sensitive as rats to the same dose

expressed as mg/kg/day. These values differ
Ch. 5–Extrapolation From Study-Generated Data to Estimates of Human Risk ● 171

Table 34.—Comparison of Tumor Rates in Laboratory Test Animals and Humans

Following Lifetime Exposures to Comparable Amounts of Each of Six Agents

(comparison based on mg agent/kg body weight /lifetime)

Animal tumor Human tumor Relative tumor

Chemical Test animal site(s) site rat e

a

Benzidine Mouse Liver Bladder ca. 1

Rat Bladder

Cigarette smoking Mouse Lung Lung ca. 1

Hamster Larynx

N, N-bis(2-chIoroethyl) -2-naphtylamine Mouse Lung Bladder ca. 1

Aflatoxin B, Mouse Liver Liver ca. 10

Rat Liver

Diethylstilbestrol

(DES) Mouse Mammary Daughters’ re- ca. 50

productive tract

Mouse Cervix and

vagina

Vinyl chloride Mouse Lung Liver ca. 500

Mouse Mammary

Rat Kidney

Rat Liver

ar~lativ~ ~U~Or ~at~ = ~mor Incidence predicted from~ost Sensltlve animal sPecles — ————

tumor incidence observed In humans

SOURCE Adapted from National Research Council (262)

from unity by a factor of 3 or less which is

assumed for doses scaled on the basis of mg/

kg/day (see table 33).

A decision about whether the reasonably

good agreement between extrapolated values

and observations (72,262) are of significance,

and whether or not these findings mean extrapolation is accurate enough for making quantitative decisions about human risks depends on

the observer. The NRC Committee (262) concluded that:

Although there are major uncertainties in extrapolating the results of animal tests to man,

this is usually the only available method . . .

Despite the uncertainties, enough is known to

indicate what dependencies on dose and time

may operate and to provide rough predictions of

induced cancer rates in human populations.

Regulating Pesticides, a report prepared by

the National Academy of Science’s Committee

on Prototype Explicit Analyses for Pesticides

(267), says that seven previous National Research Council reports have recommended extrapolating from animal data to projected

human risk, The Committee (267) took a different position and recommended that only epidemiologic data be used to estimate human risk:

OPP [Office of Pesticide Programs, EPA]

should abandon its attempts to produce numerical estimates of the effects of the use of pesticides on human mortality and morbidity except when reliable human epidemiological data

are available. In the usual case, in which major

reliance has to be placed on the results of bioassays, those results should be used to construct

indicators of the relative pathological activity of

the pesticide under review in comparison with

other pesticides and compounds.

Documented differences between the metabolism of a chemical in test animals and in humans would be very useful in any attempt at

biologic extrapolation. Poor understanding of

comparative biochemistry hampers research in

the basic biology of cancer. As research con-
172 . Technologies for Determining Cancer Risks From the Environment

tinues, knowledge of metabolic differences be- limited by strong constraints on studying metween animals and humans may provide clearer tabolism of carcinogens in humans.

direction, but such information will always be

SUMMARY

Animal tests

data that relate

or epidemiologic studies yield

cancer (or tumor) incidence to

exposure levels (dosage) of the substance under

study. The accuracy of the relation between exposure and incidence is always limited. Practical

restraints on the number of animals that can be

tested means that the data are always subject to

significant experimental error; it also means that

only relatively high incidence almost always

greater than 10 percent, can be measured in the

experiments. Epidemiologic studies may be limited by small numbers of people available for

study, or by unknown or uncertain exposure

levels. In all cases, deficiencies in experimental

design and execution may further limit the accuracy of relating incidence to dose.

Quantitative extrapolation begins with the

experimentally determined relationship between

incidence and exposure and may use one of several methods to derive an estimate of incidence

at exposure levels likely to be encountered in the

environment. When animal data are used for extrapolation one of four scaling factors can be

used to extrapolate from animal results to expected human response. The scaling factors

vary some fortyfold in the risk they project for

humans, and agreement has not been reached

about which one is most appropriate.

There is also no agreement about which

mathematical models best extrapolate from the

exposure levels measured in studies to those encountered in the environment. Linear models,

which assume that incidence is proportional to

exposure at low-exposure levels, are used by

Federal agencies. Some other organizations

favor nonlinear models in which estimates of incidence decrease faster than dose decreases. A

special feature of some models is the incorporation of a threshold, a low, but nonzero exposure

level at which the estimated incidence is zero.

Nonthreshold models, which are used by Federal agencies, associate some positive estimate

of incidence with all doses above zero.

Suggestions are frequently made that careful

inspection of available data and testing various

extrapolation models against them will allow

selection of the best model. Unfortunately data

are not sufficient to make such judgments.

Another method to decide which model is appropriate is to make projections from animal

data and compare those to observed incidence in

humans. The cases where human data are available to make comparisons are few, but the conceptually simple, linear, nonthreshold model is

reported to estimate human incidence reasonably well.

The increasing importance of short-term tests

has led to efforts to extrapolate from them to

estimates of carcinogenic risks in humans or

animals. Qualitatively short-term tests perform

well in predicting whether a substance will be

carcinogenic or noncarcinogenic in an animal

test. Quantitative agreement between mutagenic potency in short-term tests and carcinogenic potency in animal tests for carcinogenicity

is not nearly so good.
6 ●

Approaches to

Regulating Carcinogens
Contents

Page

Public Perception About Cancer and the Legislative Response . ...............175

Statutory Mandates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........176

An Example of Balancing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .........181

The Precautionary Nature of the Definitions of Toxic Risks in the Laws .. ...181

Regulatory Definitions of Carcinogens . .............................182

Degree of Protection . . 00 . . 0 . . . . . . . . . . . . . . . . . . . . ..6...... .*.**.. * 182

Agency Administrative Procedures for Carcinogen Regulation. . ..............183

The Administrative Procedures Act of 1946. . . . . . . . . . . . . . . . . ..........183

Judicial Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......184

Regulatory Reform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l84

Procedural Reforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .185

Structural Reforms Through Shifts in Oversight . . . . . . . . . . . . . . . . . . . . .. .186

Substantive Change: Deregulation . . . . . . . . . . . . . . . . . . . . . ............188

Estimates of Risk and Reduction of Carcinogenic Exposures. . ................188

Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I88

Limits to Quantitative Risk Assessment. . . . . . . . . . . . . . . . . . . . . . ........190

‘Trigger” Levels for Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Locations of Federal Carcinogenic Risk Assessment Activities . ...............192

OSTP Proposal for Decisionmaking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..194

The American Industrial Health Council. . . . . . . . . . . . . . . . . . ...........194

Representative Wampler’s National Science Council Proposal. . ...........194

Judge Markey’s Proposal for Legislative Branch Review of Risk Decisions. . . . 195

Summary Comments About Technical Panels and Study of Their

Feasibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Making Regulatory Decisions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Possible Decisionmaking Frameworks. . . . . . . . . . . . . . . . . . . . . . .........196

Feasibility and Limits of Benefit-Cost Analysis . . . . . . . . . . . . . . . . . . . . .. ..197

An Alternative to Benefit-Cost Analysis.for Making Regulatory Decisions .. ..199

Making an Unreasonable Risk Decision. . . . . . . . . . . . . . . . . . . . . . ., .. ....202

Not “Unreasonable Risks” and What to Do About Them. . ...............203

Responsibility for Making Decisions, . . . . . . . . . . . . . . . . . . . . . ..............203.

Executive Branch Decisions. . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........203

Judiciary Branch Decisions . . . . . . . . . . . . . . . . . . . . . . . . . . .............204

Directions From Congress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Regulated Carcinogens. ... , ., ... , . . . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . . . . 205

LIST OF TABLES

Table No. Page

35. Public Laws Providing for the Regulation of Exposures to Carcinogens .. ....178

36. An Example of Balancing Cancer Risk v. Revenue Loss. The FDA’s

Setting a Tolerance for PCBs in Fish. ., . . . . . . . ., ., . . . . . . . . . . . . . . . . . . .181

37. Ample Margin of Safety as Used in Two Laws . . . . . . . . . . . . . . . . . . . . .. ...183

38. Substances Regulated as Carcinogens Under Various Acts ., . . . . . . . . . . . . ..206
6

Approaches to Regulating Carcinogen;

PUBLIC PERCEPTION ABOUT CANCER AND

THE LEGISLATIVE RESPONSE

The importance of cancer in U.S. policies

about disease is illustrated by the attention

focused on cancer research. The first institute of

the U.S. Public Health Service to be devoted to

a single disease was the National Cancer Institute (NCI), established in 1937. Initially a freestanding institute, it was incorporated into the

National Institutes of Health (NIH) which was

organized in the 1940’s, Thirty-four years after

NCI’s establishment, a nearly successful effort

was mounted in Congress, in 1971, to separate

NCI from NIH and to establish a National Cancer Authority, that would have set cancer further apart from other biomedical research activities. While the National Cancer Act of 1971

was unsuccessful in establishing a new authority, it elevated NCI to bureau status, a higher

organizational level than all other institutes at

NIH until the National Heart, Lung, and Blood

Institute was also made a bureau. The 1971

legislation established a three-person cancer

panel, appointed by and responsible to the

President; no other disease has been singled out

in such a way. The attention bestowed on cancer research reflects the importance of the disease to the public. It is the number two killer in

the United States, the number one disease killer

among people younger than 55, and it is the

most dreaded disease (307).

In the 1960’s and 1970’s, public and congressional interest in cancer prevention was spurred

by associations being drawn between environmental exposures and cancer. Congressional

testimony mentioned associations between the

environment and cancer, and several laws were

enacted to provide Federal agencies with regulatory mechanisms to reduce exposures to carcinogens.

Public fear and dread of cancer is not likely to

decrease, and despite the current antiregulatory

mood, Americans still favor health and environmental regulations. A survey of 2,000 people,

commissioned by Union Carbide in 1979, found

continued public support of Government efforts

“to protect individual health and safety and the

environment.” Seventy percent of those surveyed favored stronger measures to protect

workers from cancer; 65 percent favored stronger measures to protect consumers from cancer

(352).

Concern about cancer is likely to provide impetus for continued efforts to reduce its incidence and to improve its treatment. Efforts to

improve treatment are seen as highly desirable

and excite little controversy, but efforts to

reduce cancer incidence by regulatory intervention generate great passion about whether the

expected benefits from the regulations justify

their costs. As is pointed out in the earlier

chapters of this report, some uncertainty is

associated with estimates made of the cancer

risk posed by particular exposures. Part of the

controversy about regulatory intervention,

whether it is worth it or not, flows from those

uncertainties, but controversy also stems from

the fact that the regulations bring two societal

goals into conflict. The majority of people want

protection from carcinogenic risks, and at the

same time want to reduce regulatory costs and

burdens. Choosing between these two goals or

reaching compromises between them will remain an important point of contention in policies about the control of cancer.

Several Federal agencies administer regulatory programs for the control of carcinogenic

and other health risks to humans from chemical

substances. These programs differ in their objectives and regulatory authority. Some were designed by Congress to deal with several different

types of risks, including carcinogenic risks, in

175
176 Technologies for Determining Cancer Risks From the Environment

the workplace or in consumer products. Others cerning the existence and magnitude of risk.

were designed to protect humans and the envi- This chapter first discusses statutory mandates

ronment through control of toxic substances in related to carcinogen regulation, then moves to

air, water, and food. an examination of risk assessment issues. A

Regulatory decisionmaking for control of concluding section focuses on the process of

cancer risks to humans is guided by specific making regulatory decisions for controlling

legal mandates and administrative procedures carcinogens.

and depends on technical determinations conSTATUTORY MANDATES

Regulations of carcinogenic substances are

designed to reduce health risks. The laws that

require such regulations differ in whether they

direct regulators to consider only health risks or

to consider both health risks and other factors.

The other factors to be considered may include

the costs of reducing the exposure and the costs

of foregone benefits from reduced availability of

the substance.

Table 35 lists 10 laws under which some action has been or may be taken to reduce exposure to carcinogens. Of the applicable statutes, the Federal Food, Drug, and Cosmetic Act

(FDCA), the Clean Water Act (CWA) of 1977,

and the Toxic Substances Control Act (TSCA)

specifically mention carcinogens. The remaining

statutes provide for regulating all toxics, and

carcinogens are included in the more general

term. The list includes the laws most often discussed in relation to carcinogens but not all laws

under which carcinogens might be regulated.

For instance, laws governing transport of hazardous substances might be used to regulate carcinogens, and the U.S. Department of Agriculture regulates carcinogens in poultry and meat.

The earliest laws reflecting congressional concern about toxics centered on the food supply.

Those laws, enacted around the turn of the century, established the Food and Drug Administration (FDA). In line with the importance society attaches to a safe food supply, the first law to

apply directly to carcinogens was aimed at carcinogenic food additives. The Delaney clause,

incorporated into the Food Additives Amendment of 1958, forbids the incorporation into

food of any additive shown to induce cancer in

humans or other animals.

The late 1960’s and the 1970’s saw the identification of carcinogens in various parts of the environment, and Congress provided legislative

authority to regulatory agencies to reduce such

exposures. The number and diversity of laws

produces a “balkanized” Federal regulatory effort. Whether or not carcinogen regulation

would be better accomplished under fewer,

broader laws is a question worthy of consideration, but it is beyond the scope of the present

assessment.

Bases for the Laws

Although many of the laws deal with other

toxics in addition to carcinogens, the discussion

here will focus on carcinogens to the exclusion

of other health and environmental risks. The existence of the laws clearly states that Congress

has seen cancer risks as deserving Government

attention. At the same time, despite the fact that

some of the laws are attacked as proposing an

unobtainable risk-free society, Congress has

recognized that cancer-risk management can

sometimes involve balancing and comparing of

risks against other societal goals. The 10 laws in

table 35 can be divided into “risk-based laws”

(or zero-risk laws) which allow no balancing of

health risks against other factors, “balancing

laws” which require balancing of risks against

benefits of the substance, and “technologybased laws” which direct regulatory agencies to

impose specified levels of control (306).
Risk-Based Laws

For this discussion, “risk-based” refers to legislation that provides for regulations to reduce

risks to zero without considering other factors.

The primary example is the Delaney clause

which specifies that carcinogenic food additives

are to be eliminated from the food supply. Section 112 of the Clean Air Act (CAA) and section

307(a)(4) of CWA call for the reduction of exposures to levels which allow an “ample margin

of safety. ” Because Federal agencies do not accept threshold levels below which carcinogens

pose no risk, strict interpretation of “ample

margin of safety” would also require reductions

to zero exposures. The Resource Conservation

and Recovery Act (RCRA) is also risk-based,

but no regulation about carcinogens has yet

been issued under it.

When it enacted the Delaney clause, Congress

was aware that over 1,000 substances were present as additives in the U.S. food supply. Many

of those substances had been poorly tested (if at

all) for acute toxicity and hardly any had been

tested for chronic toxicity. Congress recognized

that some of the additives might pose health

problems, and the Delaney clause reflects its

conclusion that no benefit could militate against

banning a carcinogenic additive.

The most recent application of the Delaney

clause was the proposed removal of saccharin

from the “generally recognized as safe” (GRAS)

list of food additives. This action, based on the

finding that saccharin causes bladder cancer in

rats, would then have resulted in the ban of saccharin from use as a food additive (282). Few

people question that saccharin is a rat carcinogen, and the Delaney clause is clear: Saccharin

should be removed from the market on the basis

of the animal study. Peter Hutt, former General

Counsel of FDA, points out that a zero-risk approach, such as the Delaney clause, may work

reasonably well so long as there are substitutes.

When no substitute is available, controversy

flares, It flamed in the case of saccharin.

Because FDA had banned cyclamates on the

basis of animal tests in 1969, the banning of saccharin would have meant that there would be no

nonnutritive sweetener on the market. No one

could have the pleasure of sweetness without the

cost of calories. Citizens who objected to the

ban, aided by postage-paid postcards inserted

into cartons of saccharin-sweetened soft drinks,

deluged Congress with mail. Congress delayed

the imposition of the saccharin ban and called

for more studies. In 1980, it continued the

delay.

At the request of Congress, both OTA (282)

and the National Research Council (NRC) (269)

reviewed the scientific data and conclusions

about saccharin and agreed with the FDA decision that saccharin is a carcinogen. The congressional decision to forestall action on saccharin can be viewed as the Congress reopening

discussion about its earlier decision that benefits

of carcinogenic food additives could not be

weighed against their risks. It is aware of the

evidence of risks (from animal studies) and

benefits (from public outcry), and by delaying

the ban, it is giving weight to the benefits.

Whether the saccharin moratorium presages

an eventual voiding of the Delaney clause is an

open question. Congress may retain the Delaney clause but, from time to time, exercise its

prerogative to overrule agency decisions when it

decides that benefits, whether measured or not,

outweigh risks.

Comments are sometimes heard that the Delaney clause was appropriate for the state of

knowledge in 1957 when it was enacted, but that

times have changed. It is said that at that time

there was general agreement that few substances

were carcinogenic and that those few could be

eliminated from commerce with little difficulty.

However, more and more substances, including

many useful and some apparently essential

ones, have been identified as carcinogens. Some

people make a connection between these discoveries and the apparent turning away from riskbased laws such as the Delaney clause.

Despite the fact that some of the laws written

in the 1970’s were technology-based or balancing (see below), section 112 of CAA, 1970, and

RCRA, 1976, are risk-based. They direct that

risks to health be reduced or eliminated without

specifically calling for consideration of other

factors, An important consideration in these
178 ● Technologies for Determining Cancer Risks From the Environment

Table 35.—Public Laws Providing for the Regulation of Exposures to Carcinogens

Definition of toxics or

Legislation hazards used for regula- , Agents regulated as carcinogens Basis of the

(Agency) tion of carcinogens Degree of protection (or proposed for regulation) legislation Remarks

Federal Food, Drug

and Cosmetic Act:

(FDA)

Food Carcinogenicity for additive defired by Delaney

Clause

No risk Permitted, ban of

additive

21 food additives and colors Risk

Contaminants “necessary for the protection of public health. .”

sec. 406 (346)

Three substances—aflatoxin, PCBs, Balancing

nitrosamines

Carcinogonicity is defined

as a risk

Risks and benefits of drug

are balanced.

Drugs Not determined Balancing

Cosmetics “substance injurious under

conditions of use prescribed. ”

Action taken on the basis

that cosmetic is

adulterated.

Not determined Risk. No health

claims are allowed

for “cosmetics.” If

claims are made,

cosmetic becomes

a “drug.”

Occupational Safety

and Health Act

(OSHA)

Not defined in Act (but

OSHA Generic Cancer

Policy defines carcinogens

on basis of animal test

results or epidemiology.)

“adequately assures to the

extent feasible that no

employee will suffer

material impairment of

health or functional

capacity. .” sec. 6(b) (5)

20 substances Technology (or

balancing)

Clean Air Act (EPA)

Sec. 112 (stationary sources)

Basis of the Airborne Carcino

gen Policy

“an air pollutant. . which

. . . may cause, or contribute to, an increase in mortality or are increase in serious irreversible, or incapacitating reversible, illness.” sec 112(a) (1)

‘(an ample margin of safety

to protect the public

health. .“ sec. 112(b) (1) (B)

Asbestos, beryllium, mercury, vinyl Risk

chloride, benzene, radionuclides, and

arsenic (an additional 24 substances

are being considered)

Technology Sec.

202(b) (4) (B) includes a risk-risk

test for deciding

between pollutant

that might result

from control attempts.

Sec. 202(b) (4) (A)

Specifies that no

pollution control

device, system,

or element shall

be allowed if it

presents an unreasonable risk

to health, welfare or safety.

Sec. 202 (vehicles) “air pollutant from any

. . . new motor vehicles. .

or engine, which. . . cause,

or contribute to, air pollution which may reasonably

be anticipated to endanger

public health or welfare.”

“standards which reflect

the greatest degree of emission reduction achievable

through. technology

. . . available. .” sec. 202(b)

Diesel particulate standard

(3)(a) (1)

1(c) (2)

sec. 202A(a) (1)

Sec. 211 (fuel add- Same as above (2

itives)

l(c) (l)). Same as above (2

(a)).

Balancing.

Technology-baaed

with consideration

of costs, but

health-based in

requirement that

standards provide

ample margin of

safety.

A cost-benefit

comparison of

competing control technologies

is required.

—

Clean Water Act

(EPA) Sec. 307

Toxic pollutants Iisted in

Committee Report 95-30 of

House Committee on Public Works and Transportation. List from consent

decree between EDF,

NRDC, Citizens for Better

Environment and EPA.

Defined by applying BAT 49 substances listed as carcinogens Technology

economically achievable by CAG.

(sec. 307(a) (2)), but effluent

levels are to “provide(s) an

ample margin of safety.”

(sec. 307(a) (4))

Federal Insecticide,

Fungicide, and Rodenticide Act and

the Federal Environmental Pesticide

Control Act (EPA)

One which results in “unreasonable adverse effects

on the environment or will

involve unreasonable

hazard to the survival of a

species declared

endangered . .”

Not specified. 14 rebuttable presumptions against Sec. 2(bb) Balanc- “Unreasonable

registrations either initiated or com- ing. adverse effects”

pleted; nine pesticides voluntarily “unreasonable ad- means “unreawithdrawn from market. verse effects. .” aonable risk to

man or the

environment taking into account

the economic,

social, and environmental

costs and

benefits. . .”
C/I. 6—Approaches to Regulating Carcinogens ● 179

Table 35.—Public Laws Providing for the Regulation of Exposures to Carcinogens (Continued)

Definition of toxics or

Legislation hazards used for regula- Agents regulated as carcinogens Basis of the

(Agency) tion of carcinogens Degree of protection (or proposed for regulation) Iegislation Remarks

Resource Conservation and Recovery

Act (EPA)

Safe Drinking Water

Act (EPA)

Toxic Substances

Control Act (EPA)

Sec. 4 (to require

testing)

Sec. 6 (to regulate)

Sec. 7 (to commence civil action

against Imminent

hazards)

Federal Hazardous

Substances Act

(CPSC)

Consumer Product

Safety Act (CPSC)

One which “may cause, or

significantly contribute to

an Increase in mortality or

an increase in serious irreversible, or Incapacitating

reversible, illness; or, pose

a. hazard to human

health or the environ.

ment. .” sec. 1004(5) (A)

(B)

“contaminant(s)

which. . may have an

adverse effect on the

health of persons.” sec.

1401(1) (B)

substances which “may

present an unreasonable

risk of injury to health or

the environment. ” sec. 4(a)

(1) (A) (i)

substances which “present(s) or will present an

unreasonable risk of injury

to health or the environment,” sec. 6(a)

“imminently hazardous

chemical substance or

mixture means a.

substance or mixture

which presents an imminent and unreasonable risk

of serious or widespread

injury to health or the environment. ”

“any substance (other than

a radioactive substance)

which has the capacity to

produce personal injury or

illness “15 USC sec.

“products which present

unreasonable risks of injury. in commerce,” and

“ ‘risk of Injury’ means a

risk of death, personal injury or serious or frequent

injury. ” 15 USC sec. 2051

“imminently hazardous

consumer product’ means

consumer product which

presents Imminent and

unreasonable risk of

death, serious illness or

severe personal in jury.” 15

USC sec. 2061

“that necessary to protect

human health and the environment. .” sec. 3002-04

“to the extent

feasible. (taking costs into consideration). .” sec.

1412(a) (2)

Not specified

74 substances proposed for Iisting as

hazardous wastes

Trihalomethanes, chemicals formed by

reactions between chlorine used as

disinfectant and organic chemicals.

Two pesticides and 2 metals classified

as carcinogens by CAG, but regulated

because of other toxicities.

Risk. The Administrator can order

monitoring and

set standards for

sites.

Six chemicals used to make plastics Balancing: "unreapliable. sonable risk”

Based on degree of protection in sec. 6

Balancing

“to protect adequately PCBs regulated as directed by the law.

against such risk using the

least burdensome requirement” sec. 6(a)

“establish such reasonable

variations or additional

label requirements.

necessary for the protection

of public health and

safety “15 USC sec.

“standard shall be Five substances: asbestos, benzene,

reasonably necessary to benzidine (and benzidine-based dyes

prevent or reduce an and pigments), vinyl chloride, “tris”

unreasonable risk of in jury.”

15 USC sec. 2056

Balancing. “unreasonable risk. ”

Risk “Highly toxic”

defined as

capacity to

cause death,

thus toxicity

may be limited

to acute toxicity.

Balancing: “unrea- Standards are to

sonable” be expressed,

wherever feasible, as performance require.

ments.

SOURCE Office of Technology Assessment
180 ● Technologies for Determining Cancer Risks From the Environment

two laws is that they deal with pollutants.

Pollutants benefit no one, and their reduction or

elimination improves the environment and public health.

A problem arises because eliminating the pollutants costs money. Furthermore, in the case of

carcinogens, the evidence that a substance poses

a risk is not always accepted by everyone. As a

result, the cost of reducing exposure to a pollutant is often offered as an argument against the

projected health benefits expected from regulation, and suggestions are made that the costs be

considered against the benefits before regulation, even in cases where the law does not call

for such considerations.

Balancing Laws

The “balancing laws, ” such as the Consumer

Product Safety Act (CPSA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA),

and TSCA, put a qualifying word, such as “unreasonable” in front of the word “risk. ” This

construction implies that some risks are to be

tolerated, and, in practice, means risks from a

substance are to be weighed against other factors in the process of deciding whether and how

to regulate. TSCA requires that “the benefits

. . . for various uses, . . . the economic consequences of the rule, . . . the effect on the

national economy, small business, technological innovation, the environment, and public

health” [TSCA sec. 6(c)(D)] be considered in deciding whether a substance does or does not

pose an unreasonable risk.

Balancing is equated with some kind of comparison of benefits and costs, but none of the

laws explicitly requires formal benefit-cost

analysis. For instance, the Committee on Interstate and Foreign Commerce Report (65) on

TSCA says that, “a formal benefit-cost analysis

under which a monetary value is assigned to the

risks” is not required. And a court decision

about an action taken under CPSA declared that

the Consumer Product Safety Commission

“does not have to conduct an ‘elaborate costbenefit analysis’ to conclude that ‘unreasonable

risk’ exists” (145).

All of the laws provide for the regulation of

carcinogens which threaten human health. In

the case of the balancing laws Congress requires

that other considerations be balanced against

the health risk. In practice health risk signals an

agency that it should consider regulation; the

stringency of that regulation is at least partially

determined by balancing.

Technology-Based Laws

CWA and CAA are, in general, technology

based. For instance, CAA directs the Administrator of the Environmental Protection, Agency

(EPA) to reduce particulate emissions to some

percentage of existing levels. The regulations

may be “technology-forcing” because new techniques may be required to achieve the reduction. In other cases, the laws specify that pollution control is to be achieved by using “best

practical technology” (BPT) or “best available

technology” (BAT). Such regulations do not

force new technology, but bring all control efforts up to standards established by existing

control technologies.

An important consideration of the technology-based laws is that EPA has not yet been required to produce studies to show that the imposition of new standards will improve public

health. Imposition of the standards reduces exposures, and in the case of carcinogens, given a

nonthreshold approach to carcinogenic risks, it

follows that reducing exposures should improve

public health.

The Occupational Safety and Health Act

(OSH Act) requires:

The Secretary, in promulgating standards

. . . shall set the standard which most adequately assures, to the extent feasible, on the basis of

the best available evidence, that no employee

will suffer material impairment of health or

functional capacity . . . . In addition to the attainment of the highest degree of health and

safety protection for the employee, other considerations shall be . . . the feasibility of the standards . . . (OSHA; sec. 6(b)(5))

In the sense that feasible has a technological

meaning, the OSH Act can be considered as a
Ch. 6—Approaches to Regulating Carcinogens ● 181

technology-based law. However, the Supreme

Court may issue a decision in a case involving

an OSH Act standard for exposure to cotton

dust, that will determine whether or not benefits

and costs have to be calculated to justify the

standard. That case may not be heard since the

Occupational Safety and Health Administration

(OSHA) has withdrawn its proposed standard.

Freeman (131) has argued that the “technology-based” laws require balancing, pointing

out that BPT implies balancing. How else can

“practical” be defined? Likewise, deciding what

is BAT involves balancing costs of the technology against the expected gains.

Doniger (95) cites a significant difference between technology-based and balancing laws. He

suggests that once a hazard is identified under a

technology-based law, the next step is to determine the best means to control it and then decide if there are any compelling reasons to back

off from the best means. Under a balancing law,

he says, once a hazard is identified, the next step

is to quantify the risks it presents in order to

balance those against costs of control.

The tripartite division of the laws—risk, balancing, technology—while useful, does n ot

neatly describe all the laws when subjected to

closer inspection. Complex laws contain sections that have different bases, and carcinogen

regulations are generally developed under riskbased or balancing sections of the those laws.

An Example of Balancing

FDA can balance costs and benefits in regulating carcinogens in food except when the carcinogen is a food additive. An example of that

balancing is the FDA (124) regulation of polychlorinated biphenyls (PCBs) in fish. FDA considered three possible levels for PCBs in fish

from the Great Lakes (see table 36). Fish that

contain PCBs up to the FDA-established tolerance level can be sold; those having more PCBs

cannot be sold.

Few (perhaps no) people dispute that PCBs

are a human health hazard. The acceptance of

that fact is amply demonstrated by TSCA (sec.

6(e)) directing that PCBs be regulated. The inTable 36.—An example of Balancing Cancer Risk v.

Revenue Loss. The FDA’s Setting a Tolerance

for PCBs in Fish

Estimated

Proposed tolerance Projected cancer loss of

ppm cases/vear revenue

5 46.8 $ 0.6 million

2 34.3 5.7 million

1 21.0 $16.0 million

formation in table 36 may illustrate that once a

risk is accepted as real, i.e., worthy of regulatory attention, the stringency of the regulation

is set by economic or other factors. It is reasonable to assume that more cancer would result

from PCBs at 5 ppm than at 1 ppm, but given

the uncertainties of quantitative risk assessment, it is difficult or impossible to accept that

the projected number of cases is accurate.

Nevertheless, FDA decided that “the balance between public health protection and loss of food

is properly struck by a 2-ppm tolerance. ”

The Precautionary Nature of the

Definitions of Toxic Risks in the Laws

Reduction of exposures to carcinogens are intended to prevent cancer. Given the long latent

period between exposure and overt disease

symptoms, prevention must depend on the identification of carcinogens in test systems. The

alternative, waiting for human evidence of carcinogenicity exposes some portion of the population to a carcinogen. Even if the substance is

then withdrawn completely, the legacy of the

exposure would be a continuing number of cases

as some of the exposed people develop cancer.

Reflecting these concerns, the definitions of toxic substances under which carcinogens are regulated do not require evidence of human disease.

In accepting evidence from other sources, each

of the laws is precautionary.

The Delaney clause is most direct; it accepts

evidence of animal carcinogenicity as sufficient

to ban a food additive. Section 112 of CAA calls

for regulation of pollutants that “may cause . . .

[an] increase in mortality;” RCRA and the Safe

Drinking Water Act also use a “may” construc-
tion in defining toxics. TSCA directs EPA to require testing of new chemicals which “may present an unreasonable risk” (sec. 5), but has a

more stringent, but still precautionary phrase,

“presents or will present an unreasonable risk”

in section 6 which authorizes regulating a toxic

substance already present in commerce.

Regulatory Definitions of Carcinogens

The Delaney clause contains an operational

definition for carcinogens:

no additive shall be deemed safe if it is

found, after tests which are appropriate for the

evaluation of food additives, to induce cancer in

man or animal.

Although the other laws do not define what

properties of a substance make it a carcinogen, a

number of Federal documents (e. g., 180,279)

specify what technical results agencies will consider in deciding about carcinogenicity.

In most cases, animal data are the only basis

for decisions about carcinogenicity. Seemingly

endless arguments can be mounted about test

results: that the tested animal may not be a surrogate for humans, that the dose was too high,

that lesions in animals may not parallel human

disease states. Given the current state of knowledge, those argument cannot be answered to

everyone’s satisfaction. In the absence of agreement among all concerned parties, agency statements about methods to be used in making decisions about carcinogenicity represent the Federal Government’s position. It can only be expected that the methods will remain disputed

until basic science provides more information

about carcinogenic mechanisms and human response to carcinogens.

Degree of Protection

A balance between health and other considerations is struck by defining the degree of protection in each law. The Delaney clause, in which

the balance is on the side of health, requires

banning and the maximum degree of protection.

The other definitions of degree of protection

in table 35 are not so clear, and at least one

posed a difficult task for a regulatory agency.

Section 112 of CAA is the basis for EPA’s (111)

proposed airborne carcinogen policy. It directs:

The Administrator shall establish any such

standard at the level which in his judgment provides an ample margin of safety to protect the

public health from such hazardous pollutant

[CAA sec. 112(b)(l)(B)].

The proposed airborne carcinogen policy

(111) states that EPA has, “as a matter of prudent health policy, taken the position that in the

absence of identifiable effect thresholds, carcinogens pose some risk of cancer at any exposure above zero. ” The position that no threshold

can be assumed for carcinogenicity makes it impossible to achieve an “ample margin of safety”

unless zero emissions are imposed. However,

EPA also decided that zero emissions for some

substances would impose a too heavy economic

burden, and that such controls were not what

Congress had in mind. EPA solved this problem

by proposing that BAT controls will be imposed, and if they leave an unreasonable residual risk, further controls will be considered (111):

Final standards for source categories presenting significant risks to public health would, as a

minimum, require such sources to use best available technology to reduce emissions. If, however, the risk remaining after the application of

best available technology is determined to be

unreasonable, further control is required.

A striking contrast in the use of the words

“ample margin of safety” is seen in comparing

CAA (sec. 112) and CWA (sec. 307). Under

CWA, the first level of regulation is to be BAT

which is also the language chosen for the proposed airborne carcinogen policy, after it had

been concluded that an “ample margin of safety,” the language of section 112, was unattainable. If after BAT has been applied, residual

risk remains, “effluent standards” may be written to reduce effluents to achieve “an ample

margin of safety” (see table 37).
Ch. 6—ApproacheS to Regulating Carcinogens ● 183

Table 37.—Ample Margin of Safety as Used in Two Laws

Clean Air Act Clean Water Act

Level of protection Sec. 112(b) (1) (B) “ample Sec. 307(a) (2) in accordance

margin of safety to protect with sections 301(b) (2) (A) and

the public health. . .” 304(b) (2) sets “effluent limitations” according to BATa

.

Regulatory language No threshold level is

assumed for carcinogens

and an ample margin of

safety is unattainable

therefore BATa is imposed.

What happens if BATa Stricter measures can be em- Sec. 307(a) (4) an “effluent stanis judged inadequate? ployed to control residual un- dard” can be promulgated to

reasonable risk. provide “an ample margin of

safely. ”

aBe5t available technology

AGENCY ADMINISTRATIVE PROCEDURES FOR

CARCINOGEN REGULATION

The Administrative Procedures Act

of 1946

The executive branch of Government administers hundreds of different laws. Agency procedures for carcinogen regulation as well as

other subject areas are substantially dictated by

the Administrative Procedures Act of 1946, specific formulas mandated by Congress within

certain enabling statutes, and, in certain cases,

by Executive orders. To varying degrees these

formulas aim to safeguard individual rights and

due process, while balancing potentially conflicting national goals and policies.

The Administrative Procedures Act (APA)

was passed in 1946 after more than 10 years of

painstaking study and drafting. Since then,

there has been no major reform of regulatory

procedures. According to Senator McCarran

(228), who supported and explained the bill

before the Senate, its purpose is to:

. . . improve the administration of justice by

prescribing fair administrative procedure . . . .

[it] is a bill of rights for the hundreds of

thousands of Americans whose affairs are controlled or regulated in some way or another by

agencies of the Federal Government. It is designed to provide guaranties of due process in

administrative procedures.

APA is generally applicable to all regulatory

agencies and sets forth required procedures for

agencies to follow when they engage in rulemaking (e. g., rules which set standards) and adjudication (e.g., licensing). The procedures involved may range from those which allow informal, mostly written, decisions without prior

hearings, to those which require formal adjudicatory hearings complete with the right to

cross-examination. While APA contains no specific guidance on informal decisionmaking requirements, different levels of procedural detail

have developed depending on the kinds of issues

involved. As has been noted:

In terms of ordering the procedural values,

one might organize (categories of administrative

decisions) on a scale of maximum to minimum

procedures. At the top of the scale, the hearing

procedures employed may come close to the full

adjudicative model, since the issues at stake

resemble those decided in the civil or criminal

process. Toward the bottom of the scale (e.g.,

planning and policy making) there may be few,

if any, procedural requirements . . . . Even in

these categories, however, certain procedural ingredients appear; in effect, notice and reasons

requirements approximate a minimum procedural model (355).

Most of the agencies discussed in this study

use “informal rulemaking” to make regulatory
decisions. Therefore, the minimal procedural requirements apply of providing public notice of

proposed and final rules, and an opportunity

for affected interests to comment. However,

specific procedural requirements are imposed by

some enabling statutes. TSCA, for instance,

provides an opportunity for an informal hearing

with cross-examination as a part of the rulemaking process. It goes beyond the more simplified

APA informal rulemaking, but does not go as

far as to require APA formal rulemaking procedures.

Judicial Review

APA and some enabling statutes provide for

judicial review of the process by which agency

decisions are made. In the case of informal

rulemaking, the tendency is to require that

agency performance not be, “arbitrary, capricious, an abuse of discretion, or otherwise not

in accordance with law” (5 U.S. C. sec. 706).

Judicial review then examines the agency record

to see whether the agency has provided notice,

responded to comments, and given reasons for

its actions to the public.

A more stringent judicial review is applied to

formal rulemaking. In those cases, the court

may “set aside agency action, findings, and conclusions found to be . . . unsupported by substantial evidence” (5 U.S. C. sec. 706). The court

must decide whether or not the agency record

contains substantial evidence to support the

proposed action, but there is the presumption

that the court will defer to agency expertise on

technical matters contained in the record.

There is a tendency for judicial review of informal rules under the “arbitrary and capricious” standard to be increasingly stringent to

the degree that it is converging on the “substantial evidence” standard prescribed by APA for

judicial review of adjudicatory and formal rulemaking decisions (20). The reasonable conclusion is that both standards are coming to mean

the same thing in terms of agency accountability

when subjected to judicial review. As recently

noted by Judge McGowan (231):

If you’re raising the question of the difference

between arbitrary and capricious review and

substantial evidence in the record, I think the

judiciary is finally having to accept the fact that,

because Congress has used them so loosely and

so interchangeably, we have to assure ourselves

that there is very little difference, if any, between them.

The practical effect of this merging of judicial

review standards is to require closer judicial

scrutiny of agency records and evidence in all

reviewable actions. Some argue that agency

flexibility and innovation, even to the extent

allowed by APA, to meet the particular situation of each case has been almost eliminated by

the threat of more critical judicial review. There

is some concern that these developments have

caused confusion in the courts and agencies, as

well as worked considerable mischief on procedural regularity and the unifying function that

APA was originally designed to perform for all

branches of government and the public (355).

As the subject matter of regulation becomes

increasingly complex, agencies are required to

work more and more with incomplete or approximate data. Scientific uncertainty, compounded by the need to balance and value often

conflicting goals, has raised questions about the

continued workability of the present regulatory

framework.

Regulatory Reform

The following remarks reflect some of the

frustrations with the present system which are

feeding the calls for reform. In a paper presented

before the National Conference on Federal Regulation, September 1979, Richard Neustadt,

then-Assistant Director of the White House Domestic Policy Staff, observed (275):

[The 1946 Administrative Procedures Act]

predated most of the health and safety programs, concentrated on issues of procedural fairness, and took little account of the problems of

economic impact and inconsistent policies.

Cutler (76), in expressing the views of the

American Bar Association Commission on Law

and Economy, has charged:
[W]e have a regulatory system in which . . .

the buck stops nowhere. We pursue each of our

numerous and conflicting and competing goals

with single-minded devotion regardless of the effect of one upon another.

Numerous regulatory reform proposals have

been generated during the past few years, creating a widespread attack on the existing Federal

regulatory system. The lack of effective balancing mechanisms in light of present economic and

other national goals and policies has been raised

with increasing frequency as a major failing.

Furthermore, as observed by Costle (69), the

concern for reform extends to cancer regulation:

There is no question about the need for better

management of the regulatory process. For example, I will be announcing in the next several

days a national policy on the regulation of carcinogens [306]. There are 21 statutes on the

books that authorize the regulation of carcinogens. Thus, the necessity of having a consistent

national policy is self-evident.

But the issue of regulating carcinogens also

illustrates a larger point, which is that we have

not had a national road map of the cumulative

effect of regulation, nor of where that regulation

is taking us in terms of conflicting national

goals . . . [We] have lacked a systematic way of

tracking, effectively and intelligently, the multitude of regulatory activities that are ongoing

every day.

Many of the recent regulatory reform proposals have called for substantive change

through deregulation or severely restricted

regulation.

Procedural Reforms

One category of reform proposals focuses on

procedural improvements within the existing

regulatory framework to make regulation more

efficient, effective, and responsive to public

needs. Through various means these efforts aim

to improve agency administrative procedures,

agency analytic and management capability,

and public input for better regulatory decisionmaking. The executive branch, in the present

and in previous administrations, has acted to

improve the procedure through Executive orders. Legislative reforms are proposed in Congress.

Executive Order No. 12044 (Under President

Carter) and No. 12291 (Under President

Reagan)

In a major step toward regulatory reform at

the executive level, President Carter issued Executive Order No. 12044 in March 1978. It directed each executive branch agency to publish a

semiannual agenda of significant regulations

under review or development, to provide

greater opportunity for public participation,

and to prepare regulatory analyses on all proposed regulations that may have major economic consequences (an annual economic effect of

$100 million or more). To assist individual

agencies in meeting the goals of this order,

President Carter established the Regulatory

Analysis Review Group, to prepare reports on

particularly important proposed rules, and the

Regulatory Council, to prepare a biannual regulatory calendar and deal with areas of overlapping and conflicting regulations.

This order had a significant and controversial

impact on agencies charged by Congress with

regulating risks to health, safety, and the environment. Office of Management and Budget

(OMB) guidance encouraged the use of costbenefit and other economic analyses to resolve

health, safety, and environmental problems.

However, there was no uniform policy or guidance for dealing with the methodological limitations of cost-benefit analysis—use of discount

rates, how to value health and environmental

benefits, how to allocate costs and benefits to

different societal groups, etc. (20). In spite of the

order’s alleged faults and deficiencies, the Administrator and others at EPA, one of the agencies most experienced with this order, defended

it as an encouraging beginning to resolving regulatory conflicts and shaping agency decisions

in a manner that reflects overall policy objectives (69).

President Reagan issued Executive Order No.

12291 in February 1981. It preserved many features of the earlier order and provides for an in80-481 9 - 81 - 13
creased role of OMB and cost-benefit analyses

in deciding about regulations.

A conflict that arose under the old order is expected to continue, Some segments of society

want to know the contents of a proposed draft

regulation both when it leaves the agency and

when it returns from OMB. Presently no public

record is required of such drafts, and, in fact,

such materials cannot be disclosed under the

Freedom of Information Act. Protection of such

documents is seen as necessary for the smooth

functioning of the agencies and to allow regulators and decisionmakers to explore ideas and

positions before going to the public with them.

Resolution of the conflict between the public’s

right to information and the Government’s

desire for confidentiality may be reached in the

courts.

Legislation

In 1979, the administration transmitted to

Congress a bill that would have strengthened

the reforms enacted by Executive Order No.

12044, made them permanent, and applied them

to all regulatory agencies, including the independent regulatory commissions (S. 755). It also

would have overhauled key parts of the Administrative Procedures Act. Other bills of the 96th

Congress proposed procedural changes, some of

which paralleled portions of the administration’s bill (e.g., S. 262, S. 755, S. 1291, S. 2147,

and H.R. 3263).

Several proposals require an agency regulatory impact analysis before issuance of major

rules. Many require that the agencies set deadlines for rulemaking; and a schedule for review

of significant existing rules. There are new provisions for agency rulemaking and adjudication,

appointment of administrative law judges, and

greater involvement of the Administrative Conference. Measures to increase public input include establishment of a Government-wide program of assistance to public interveners.

The Regulatory Flexibility Act of 1980 (Public

Law 96-354) was enacted to lessen the impact of

Federal regulation on small businesses and small

Government units. This law requires, where

there is a likelihood that agency rules may have

a “significant economic impact on a substantial

number of small entities, ” that the agency

prepare annual agendas for such rules and a

flexibility analysis of each proposed rule. This

analysis is for the purpose of explaining the rationale for agency action, considering flexible

regulatory proposals, and examining alternatives which might minimize economic impact.

While the scope of this law is somewhat limited,

determined movement toward procedural

reform is clear.

Structural Reforms Through

Shifts in Oversight

Another category of reform proposals offers a

more far-reaching approach by shifting existing

regulatory authority to Congress, the courts, or

the executive branch. The proposals call for

structural reform in the sense that regulatory

authority and, ultimately, political power are

redistributed. They challenge the fundamental

role of administrative agencies as they now exist, by imposing new outside oversight and

review controls. Examples of these proposals include the legislative veto), the presidential veto,

and the Bumpers amendment.

The Legislative Veto

A major study on Federal regulation by the

Senate Committee on Governmental Affairs

during the 95th Congress recommended that

Congress substantially change its agency oversight processes to improve evaluation, coordination, and systematic review of agency programs. However, when it came to the legislative

veto, it concluded that although this approach

“may be appropriate in limited situations, the

Congress should reject use of the legislative veto

for regulatory agency rules . . . [and] should

also refrain from routinely adding a legislative veto provision to regulatory agency statutes” (63).

Nevertheless, a number of reform proposals

would enact various forms of the legislative

veto. Depending on the bill, the approach

would subject some or all agency proposed and

existing rules to congressional scrutiny, with

either House having authority to veto the rule
within a specified time (e. g., H.R. 1033, 96th

Cong.; H.R. 460, H.R. 495, H.R. 532, H.R.

1858, and S. 1463, 95th Cong. ).

Serious questions have been raised about the

efficiency of such an all-encompassing approach, particularly in complex areas of regulation, such as those dealing with carcinogens.

The legislative veto option could conceivably

result in technical decisionmaking being transferred from expert agencies to generalists in

Congress. There may be some constitutional

problems as well, concerning the separation of

powers, congressional delegation of authority,

the role of the President, and bicameralism

where only a one-House veto is required.

Increased Presidential Authority:

The Presidential Veto

Another structural reform proposal with far-

-reaching consequences would give the President

increased authority over regulatory decisions.

Again, there are a variety of forms to this proposal. One generating ongoing debate was developed by the American Bar Association (4). It

would authorize the President to direct an agency to take up or reconsider and modify certain

critical kinds of regulation, require cost-benefit

regulatory analysis, and subject the President’s

actions to limited congressional review. While

an agency would continue its normal rulemaking procedure, the President would have, in effect, final rulemaking authority over critical

areas, since he could direct the agency to reconsider, modify, or reverse its decision.

As with the legislative veto proposals, a fundamental impetus for this kind of approach is

the perceived loss of Government accountability

resulting from overly broad delegations of authority to the agencies. Because of the many often

conflicting national goals, to which the President must be responsive, and the narrower responsibility of single-mission agencies, greater

Presidential authority is seen as needed for an

effective balancing process and more responsible and accountable Government.

Questions similar to those raised with the legislative veto are again raised here. Constitutional and political issues related to overly

broad delegation of legislative authority; Presidential efficacy, particularly when overseeing

technical agencies; further delay and bureaucratic overload; and maintaining procedural

safeguards are all concerns which must be examined with this approach to regulatory reform.

Additionally, the shift in decisionmaking from

the agencies, which have technical expertise, to

individuals in the Office of the President who

may lack technical expertise, can be viewed as

inappropriate.

A Greater Role for the Courts:

The Bumpers Amendment

Some structural reform proposals would shift

power to the courts. A major example, which

continues to spark interest is the Bumpers

amendment, adopted by the Senate as a floor

amendment in September 1979 (S. 111, 96th

Cong., 1st sess., 1979). The amendment would

do two things. First, it would remove the presumption of validity that accompanies a regulation when it is challenged in court. Second, it

would require an agency to support the validity

of a rule by preponderance of the evidence, a

higher standard than either “arbitrary or capricious” or “substantial evidence. ”

The amendment is seen as an attempt to curb

problems associated with overregulation, and

the courts would play a greater role and have

greater influence. The role of the courts would

extend to both overregulation and underregulation, since the courts also would be the forum

for challenges that an agency is not regulating

vigorously enough.

Levin (206) says that application of the

amendment raises many ambiguities and difficulties of interpretation. While agencies could

still be expected to conduct normal rulemaking

activities, it appears that the proposal would require the courts to give little or no weight to an

agency’s decision. If so, the very reason for administrative agencies to retain expertise may be

undercut. The likely outcome would be more litigation and challenge of regulations. Some observers have expressed doubts about the amendment’s ability to facilitate more effective and ef-
ficient regulatory programs, especially in light

of the increased workloads to come to the Federal courts. Others are of the opinion that agencies, knowing of the judicial review to come,

would develop stronger cases.

Substantive Change: Deregulation

Some of the most drastic regulatory reform

proposals call for deregulation or severely restricted regulation. These proposals raise a

presumption against an agency’s continued existence and legislative renewal except where

there is explicit action to reauthorize.

One of the most popular concepts involved

has been labeled “sunset’’ -in other words, an

agency or function will expire by a certain date

unless there is enacted in the meantime a statute

reauthorizing the activity in question. Various

versions of regulatory sunset proposals have

been put forth for a number of years (e.g., S. 2

and S. 445, 96th Cong. ), Some would require

that every regulatory program covered by a

sunset requirement be reviewed at a minimum

once every 10 years. The most drastic would

call for termination of the program, with no

provisions to safeguard against termination by

inaction, if not authorized by Congress within

this review period, Intermediate versions would

require systematic review and reexamination of

existing programs and legislation by the authorizing committees, with no automatic termination.

The most extreme regulatory reform is outright deregulation. In such areas as airline

operations and natural gas production, this

course has been taken. Apparently, the fundamental consideration underlying deregulation

must be whether the objectives for which regulation was initiated can be accomplished by selfregulation in the marketplace. While most people view this approach as inappropriate for

health, safety, and environmental matters, commentators have written about movement in this

direction (59). For the present, the conclusions

of the Senate study (63) of Federal regulation

cited above provide insight into the question of

marketplace possibilities for self-regulation:

Generally speaking, “free market” solutions

are not, in the environmental area, a viable option. The activities of a single polluter affect

thousands and even millions of other firms and

individuals, with whom there usually are no ongoing market relationships. Such relationships

do not exist, in large part because neither firms

nor individuals have clear property rights to

environmental resources.

ESTIMATES OF RISK AND REDUCTION OF

CARCINOGENIC EXPOSURES

Risk Assessment

Recent years have seen a proliferation of

organizations devoted to the study of risk. As

examples, the National Academy of Sciences

(NAS) recently formed the “Committee on Risk

and Decision Making” that will consider how

society and its institutions might better assess,

compare, and manage health, safety and environmental risks. The National Science Foundation has an active “Risk Analysis Program” in

its Division of Policy Research and Analysis,

and several universities sponsor institutes for

risk analysis.

A number of different terms—risk assessment, risk analysis, and risk evaluation—are

used to describe the process of associating a specific risk with a substance. Figure 27 is an example of a three-step process for making an estimate of carcinogenic risk and a fourth step

which lists other factors that may be considered

in making a decision about reducing risk. The

figure shows where the methods described in

this assessment are used.

The first step, hazard identification, is necessary to separate carcinogens from other substances. Some laws, the Delaney clause as dis-
Figure 27.—Assessing Carcinogenic Risks and

Considering Other Factors in Making a Decision

about Risk Management

[U) H=ard identlficatiofl “I

laboratory studies

epidemiology

I-Qif no hazard

identified

stop

(2) Hazard evaluation

extrapolation to generate estimates of potencies and of unmeasurable carcinogenic

risks at low exposure levels

T

(3) Risk evaluation (or assessment) I

estimation of number of people exposed at

various levels combined with potencies to

produce estimates of risks to indhriduals and

populations

IQif risk is

smal I

enough

stop

(4) Risk management I

Evaluation of risk (step 3)

plus

evaluation of costs, cost-effectiveness,

benefits, risk vs risks of substitutes,

economic feasibility, technical feasibility, etc.

c)Strategy

to be

implemented

SOURCE: D!esler (81)

cussed above, require only this step to make a

regulatory decision. The second step, risk

evaluation, produces qualitative and quantitative expressions of the hazard associated with

the substance. The quantitative expressions

allow a rough ordering of hazards.

The third step, risk assessment, which can

produce a quantitative estimate of the potential

effect of the substance on humans, is limited by

all the uncertainties involved in hazard identification and evaluation. Additionally, in this

step, other uncertainties are introduced along

with the estimates of the number of people exposed and the levels of their exposure. Some

observers object to the third step because of

these many uncertainties. However, uncertainties do not make it impossible to attempt to

quantify risk assessments; they do affect the

form the assessment takes and the form in which

the result is presented.

The third step is necessary before quantitative

comparisons can be made between risks and

other factors. Such comparisons are shown in

step 4.

The critical function of step 3 is quantitative

risk assessment. The generally good agreement

that epidemiology and laboratory tests can

identify carcinogens does not extend to agreement that currently available data and risk

assessment techniques can accurately predict the

level of human risk, and the usefulness of quantitative risk assessment is argued.

Some observers view quantitative risk assessment efforts, especially when applied to chronic

health problems, including cancer, as premature. They see the techniques as uncertain, the

results they produce as potentially misleading,

and express concern that the users of the results

do not appreciate the reservations attached to

the numbers generated in quantitative risk

assessments.

The advocates of quantitative risk assessment

say that the methods are necessary to decide

which of the many identified carcinogens present intolerable risks and which do not. To
counter the argument that the techniques are imperfect, they cite the great amount of interest in

risk assessment and say that the methods are being improved.

Quantitative risk assessment is likely to take

on increasing importance in Federal decision

making about carcinogens. For instance, the requirement for benefit-cost analysis under Executive Order No. 12291 will result in greater demands for quantitative risk assessment. Additionally, the Supreme Court decision about

workplace exposure to benzene (337) apparently

requires that OSHA make some estimate of risk

to support regulations. The fact that benzene is

a carcinogen was not disputed in the case, but

the court returned the proposed standard to the

agency for reconsideration because OSHA had

not found,

. . . that the toxic substance [benzene at the level currently encountered in the workplace] . . .

poses a significant health risk in the workplace

and that a new lower standard is . . . “reasonably necessary or appropriate to provide safe or

healthful employment’’(20).

The requirement to show a “significant health

risk” will surely result in greater pressure on

OSHA to estimate the number of workers likely

to suffer ill-effects from exposures. The pressures for use of risk assessment will probably increase, and opponents will continue to voice

concern about its uncertainties.

Limits to Quantitative Risk Assessment

Rowe (316) draws attention to limits that he

sees surrounding the accuracy of quantitative

risk assessment. In particular he cites problems

with choosing an extrapolation model, the

widely variant estimates produced by the use of

different models (see ch. 5), and the problems

inherent in animal tests because of the relatively

small numbers of animals that can be tested (see

ch. 4). Rowe suggests that results of testing particular substances in short-term tests and bioassays be established as benchmarks. Then, as

other substances are tested, they can be classified as less hazardous, equally hazardous, or

more hazardous than the benchmark substances. At the same time, data about use and

exposure can be obtained, so that the number of

people at risk, along with potency, can be considered in deciding what next to do.

Importantly, in Rowe’s scheme, a next step is

to consider whether or not additional testing

might change the conclusion reached on presently available data. To facilitate making that decision, Rowe developed a statistic to allow consideration of the probability that a test will provide information that might alter a previously

made decision. Application of the statistic estimates the limits of knowledge that are attainable. Considering the limits of tests and extrapolation models will allow decisionmakers to

select additional testing only when the tests will

yield more definitive information. When that

condition does not prevail, the decisionmaker

can choose to do nothing or to consider various

methods to restrict exposures.

“Trigger” Levels for Regulation

Individuals in their private lives accept nonzero risks. In some instances larger risks are accepted, presumably, because the benefits associated with the risk-taking are also large. In

other situations, smaller risks are avoided,

again presumably, because the benefits are seen

as not worth even the small risk. Such observations lead to the suggestion that individuals balance risks and benefits in deciding which voluntarily assumed risks are “acceptable,”

Exposures to carcinogens in air, water, the

workplace, and other environments are different from voluntary risks. In few cases is it

possible for an individual to know the identity

and magnitude of the risk. In many cases, the

individual has no choice but to bear the unknown risk because contact cannot be avoided.

It is not necessary, in all cases, to quantify a

risk in order to decide it is not acceptable. An

example of such an unacceptable, unreasonable

risk is the use of thalidomide by pregnant

women. The association of that drug with children suffering multiple anatomic abnormalities

led to a suspension of its use. A more recent example was the association of a particular brand

of tampon with toxic shock syndrome. Before a

quantitative evaluation of the lifetime risk of

toxic shock syndrome was published, the manu-
facturer recalled the product. In these two cases,

substitute products were readily available, and

the cost of avoiding the risk was largely restricted to the lost sales of the manufacturers.

Regulatory agencies identify and quantify

risks, and the ability to quantify risks has produced suggestions for managing risks based on

their size. A small chance of risk can be set as a

“floor,” and substances presenting a risk less

than the floor might be considered acceptable.

Risks above the floor level would be divided into two groups. Intermediate risks would be considered for reduction, and benefits and risks

would be balanced in making a regulatory decision. Above a still higher level of risk, no balancing would be necessary, and any substance

presenting a risk of that magnitude or higher

would have to be regulated (3).

Products of a quantitative risk assessment

(see fig. 27, step 3) can be estimates of the

lifetime risk of cancer to: 1) members of the

general population; and 2) to members of highly

exposed populations. These risks are expressed

in scientific notation as 1 0

-4, 10-5, 10-6 (or as

fractions, 1 chance in 10,000, 1 in 100,000, and

1 in 1,000,000, respectively). Carcinogens differ

a millionfold in potency as measured in laboratory animals, and more potent ones are associated with higher risks (10-3) and less potent ones

with lower risks (10-7).

Albert (3) and others have suggested that substances associated with individual lifetime risks

of 10-5 might be considered as presenting risks

so low that they require no action to reduce

them further. Such low, negligible risks would

represent a “floor” on risks. An idea of the

magnitude of this risk is furnished by recalling

that a 10-5 lifetime risk means that one person of

100,000 exposed at that level is expected to

develop cancer from that exposure. Currently,

about 20,000 of every 100,000 Americans die of

cancer. Exposure of 100,000 people to a substance that increases risk by 10-5 could increase

the number of cancer deaths to 20,001. Whether

or not this number seems reasonable, it may be

important to consider that a lifetime risk of 10-5

for the U.S. population (220 million people) is

equal to 2,200 cancer cases in those people’s lifespans. The annual number of cancer deaths

from exposing the U.S. population to a 10-5 risk

would be about 30, assuming a lifespan of 70

years.

A fundamental objection to the idea that

some fraction of the population might be allowed to die because of exposure to a risk that is

viewed as acceptable is expressed in an argument called “the murder of the statistical person.” If the identity of the 30 people who died

annually as a result of a 10-5 risk were known,

there is little doubt that much greater effort

would be expanded to reduce the risk. Objections to the idea of society deciding that some

risks are negligible are raised by those who consider that statistical people as well as identified

people deserve protection.

It is apparently more difficult to suggest a

level of risk so high that it demands regulatory action than it is to suggest a level so low

that it requires none. Nevertheless, toward the

high end of the risk scale, agreement might be

reached that an exposure that produced a

lifetime risk of cancer of 10-2 (1 in 100) is so high

that the Government should regulate it as a

health risk with little or no regard for other considerations. The magnitude of this risk may be

compared to the tenfold higher chance (10-1

lifetime risk) of cancer that is voluntarily borne

by lifelong smokers (362).

Another consideration is that the low-level

risks, those of 10-5 or less, add up. If there are

ten 10-5 risks and the risks are additive, their

total risk is 10-4. (Of course, if synergism exists

among any of the 10, the combined risk from

both might greatly exceed 10-4). What is to be

done about the next identified 10-5 risk? Should

it be regulated, or should small risks, even if

there are 100 or 1,000 or more of them go unregulated?

If agreement could be reached on such limits,

risks above a certain level (10-3 to 10-2) might be

declared unreasonable no matter what, and

risks below a certain level (10-5) might be declared reasonable or acceptable or negligible. In

between, the risks that range from 10-5 up to

10-3 or 10-2 would require balancing of the risks
192 ● Technologies for Determining Cancer Risks From the Environment

and benefits to decide whether or not to

regulate.

The inaccuracy of the risk estimates alarms

many people. Crouch and Wilson (72) find

“good correlations” between cancer rates measured in animals and those detected in humans

due to exposure to the same chemicals. The

number of chemicals for which data are available is small (fewer than 20) and the “good

correlation” is good within a factor of 10 or 100.

In other words, an estimated risk of 10-5 might

be as high as 10-3 or as low as 10-7.

Deisler (80) has approached the problem of

the existence of many small risks by suggesting

that a ceiling be placed on total risk in “exposure

situations. ” He cites industrial exposure as one

situation and discusses a maximum allowable

amount of cancer that might be set as tolerable

for workplace exposures. As was pointed out

earlier, estimates for occupational contributions

to cancer vary from less than 5 percent to about

40 percent, and Deisler (80) suggests:

. . . the first interim goal should be . . . to

assure that industrially related cancer becomes

less than a truly small fraction of today’s total

cancer incidence in the United States . . .

As an example of a possible interim goal, he

suggests that workplace exposures be set so that

they account for 1.5 percent of the total cancer

burden. The 1.5 percent is only an example, and

Deisler suggests that the selection of a goal

might be negotiated in a public forum, possibly

through a congressional commission.

When a ceiling is established, the risks within

the exposure situation would be inventoried. If

total risk exceeds the ceiling, the risk would be

reduced by addressing one or more individual

exposures. This appears to be a cost-effective

system because the easiest-to-control, least

costly-to-control exposures would be attacked

first. If the inventory of risks totaled less than

the ceiling, the ceiling could be reduced. The individual exposures in the inventory are expected

to interact additively, but allowances could be

made for synergisms if they occur. The ceiling

also provides a method to deal with the identification of previously unrecognized carcinogens

in an exposure situation. Such a carcinogen

would be, as a first step, controlled to the point

that the ceiling is not exceeded.

Despite the demonstrated existence of unacceptable, unreasonable (and generally unquantitated) risks, it has been impossible to assign

“trigger” risk levels. Deciding on the “trigger,”

10

-3 or 10-2 on the high side, 10-5 or 10-6 on the

low side would be difficult, and problems with

the accuracy of the estimates and equity in that

those who most directly bear risks may not

most directly benefit are problems to be solved.

Currently, quantitative risk assessment does not

provide a tidy fix for the dilemma of deciding if

and when to regulate. At the same time the fact

that “acceptable” and “reasonable” risks are

discussed implies that not all risks are equal and

that society has the task to decide which are to

be regulated and which are not.

LOCATIONS OF FEDERAL CARCINOGENIC

RISK ASSESSMENT ACTIVITIES

Carcinogenic risk assessment involves a

group of people considering the available evidence, drawing conclusions from the data, and,

using methods they accept, deciding whether or

not the substance is carcinogenic and, in some

cases, estimating carcinogenic potency or

human risk. Groups which have prepared

statements about methods to be used in evaluating data differ in their interests and responsibilities, and their statements reflect the differences. In addition, there is much discussion

about who should consider the data, apply the

methods, and make the decisions.

Scientists in each regulatory agency now evaluate data about carcinogenicity of substances

that may be regulated by their own agency.

They may consider advice from expert commit-
tees in their decisions. The decision is then forwarded to the individual named in the appropriate law who announces the decision and his intentions to act on it.

The Office of Science and Technology Policy

(OSTP) (281) proposed a change from agencyby-agency decisionmaking. It suggested that all

carcinogenic risk determinations be made in

a single governmental body. Representative

Wampler proposed such a body in a bill he introduced; the American Industrial Health Council (AIHC) (10) and Markey (222) have also suggested central locations for making technical

decisions for regulatory purposes. These proposals differ from each other, but all have in

common a central panel of technical experts.

Panel proposals are all directed at decisions

made by or for regulatory agencies. At the research agency level, the National Toxicology

Program (NTP) has established a Peer-Review

Panel of Experts to review draft reports from its

bioassay program. The panel is to assure (273):

. . . carcinogenesis bioassays have been carried

out using the prevailing scientific state-of-theknowledge and that the interpretations and conclusions reflect a logical and accurate analysis of

the collected experimental data.

The panel can either approve draft reports or

return them to NTP for revision. If panel members disagree about whether a report and its

conclusions should be approved, a majority and

minority report can be filed. The panel is composed of 14 experts from academe, environmental groups, and industry and began meeting

in late 1980.

The issuance of the Interagency Regulatory

Liaison Group (IRLG) guidelines (180) provides

some uniformity to governmental decisions because all agencies are to use similar methods for

evaluating risks. Agencies appreciate that consideration by nonagency scientists may improve

their decisionmaking and may call upon experts

to aid them. For instance, the proposed OSHA

Generic Cancer Policy (279) allowed the Secretary of Labor to assemble a panel of Government experts to cooperate in making decisions

about carcinogens. Such interagency workgroups are a common response of the Federal

Government to complex and sensitive technical

issues.

Some legislation” requires that agency decisions be discussed with advisory groups of nonFederal experts. Under FIFRA, EPA is required

to refer any decisions to initiate a pesticide

cancellation to EPA’s Scientific Advisory Board

(SAB). SAB review comes at a point in time

after EPA has made a decision about whether or

not the pesticide presents a toxic hazard, and it

is an example of an advisory panel functioning

in a review capacity.

FDA has made extensive use of technical advisory panels. In 1962, FDA was required for

the first time to screen drugs for efficacy.

Thousands of drugs were involved, and the task

was immense. FDA asked that NAS assemble

technical panels for different types of drugs and

that the panels advise FDA about which drugs

were not efficacious. The panels were quite successful and since then, FDA has added technical

panels to advise about drugs, medical devices,

and food additives.

The augmentation of agency expertise can be

accomplished through calling on Government

or non-Government scientists. There is now no

legal requirement for such consultation in deci- “

sions about carcinogenicity, and advice can be

rejected by the agency. Seeking or requiring advice from scientists outside the agencies is the

least radical proposal for changing the current

decisionmaking system. A number of other proposals would move some parts of decisionmaking about carcinogenicity out of the agencies

altogether.

Three dimensions can be considered in setting

up a decisionmaking apparatus. The first is personnel, whether the technical experts are to be

from the Federal Government, the private sector, or both. Each of the proposals to be discussed below is specific about the organizational

association of the experts. The procedure that

might be used by the panel ranges from collegial

to adversarial. The proposals tend toward the

former pole; each provides the technical panel

with a staff to develop information for the

panel’s consideration. The power of the panel

can range from advisory to decisionmaking to
review. Most expert panels are now advisory,

and the SAB is a reviewing panel. Some of the

proposals call for the technical panel to make

the decision for the agencies, others to review

contested decisions.

OSTP Proposal for Decisionmaking

OSTP (281) divided Federal decisionmaking

about carcinogens into two phases. Phase I is

the identification and quantitative characterization of risks and encompasses steps 1 and 2 and

part of 3 in figure 27. Phase II is making the

regulatory decision to control the identified and

characterized risk. OSTP proposes that phase I

activities for all agencies be brought together

and located within NTP.

The current responsibilities of NTP do not include phase I judgments for regulatory decisions. However, OSTP argues that just as NTP

has a centralized coordination role in toxicological research so should it have a central role in

interpretation of data.

Gilbert Omenn, an author of the OSTP paper

(281), insists that decisionmaking about carcinogenicity should remain the responsibility of

Federal officials. He makes the point that laws

dealing with carcinogens are designed to protect

public health and that Federal officials are entrusted with responsibility for administering the

laws.

Having a panel of Federal officials decide

about carcinogenicity is a major difference between the OSTP proposal and the proposals

from AIHC and Representative Wampler. The

latter two proposals centralize decisionmaking,

but they would delegate carcinogen decisionmaking authority to new non-governmental

organizations which would include non-Federal

experts.

The American Industrial Health Council

Science Panel Proposal

The AIHC (10) proposal for a science panel

draws a distinction between scientific (“Phase

I“) and regulatory (“Phase II”) decisionmaking

as does the OSTP proposal. The science panel

would be composed of “the best scientists

available” and located centrally within Government or elsewhere. The panel would review existing data and not conduct or control research.

Briefly, when a regulatory agency reached the

point of considering regulatory action against a

chemical, it would bring its data and conclusions about carcinogenicity to the panel. The

panel would solicit additional data from industry, public interest groups, and other Government agencies and review all such data. It would

assess the evidence and communicate its conclusions to the agency about whether or not the

substance was a carcinogen. If sufficient exposure information and dose-response data

were available, the panel would also evaluate

the human hazard and risk posed by the carcinogen.

In the AIHC proposal, the panel would have

to reach a decision within a certain time limit

which would assure that it worked to a schedule. The panel would consider only scientific

questions and its findings would not be binding.

An agency could reject the panel’s conclusions

by explaining its reasons for rejection.

AIHC recommends that Congress establish a

science panel consisting of 15 members who

would assemble from time to time to consider

data. It could appoint ad hoc members to workgroups to consider particular cases, and it

would be provided with full-time professional

staff to manage its workload.

Representative Wampler’s National

Science Council Proposal

Representative Wampler’s bill to establish a

National Science Council (NSC) was introduced

on February 13, 1980 (H. R. 6521) and reintroduced as H.R. 638 on January 5, 1981. It would

establish a 15-member council to review decisions concerning chemical toxicity. A company

or individual who objected to an agency’s

assessment of toxicity during the agency’s adjudication could request NSC review of the

agency decision. Subjects of meetings of NSC

would be announced in the Federal Register and

open to the public except when trade secrets or

confidential information were discussed. The

bill offers amendments to CPSA, FDCA, the
Federal Meat Inspection Act, the Poultry Products Inspection Act, the OSH Act, and TSCA.

The amendments would make the decisions of

NSC final with respect to scientific fact under

those laws.

Mr. Wampler’s proposal stipulates that NSC

members would be appointed by the President

to full-time Federal posts for 2 years and have

appropriate staff support. This full-time service

differs from AIHC’s proposal. The AIHC Science Panel would convene “periodically to

assess materials, ” but its members would maintain their usual employment while serving.

Judge Markey’s Proposal for

Legislative Branch Review

of Risk Decisions

Each proposal so far discussed—convening

of Federal committees, non-Federal advisory

groups, or creation of scientific boards within or

outside of the Government—seeks to improve

decisionmaking before regulations are written.

A strikingly different idea has been advanced by

Judge Howard Markey of the U.S. Court of

Customs and Patent Appeals.

Markey (222) proposes no change in the way

agencies make decisions about carcinogenicity

and regulations. However, he does propose that

OTA, as an agency of Congress, review agency

decisions about risks. The review would be initiated if a regulated industry or a public interest

group objected in court to a regulation on the

basis that the agency had made a mistake in

science.

Markey goes on to say that if OTA or some

other agency designated by Congress cannot

reach an agreement about the correctness of the

agency decision about risk, “OTA would turn to

Congress, where the final decision on acceptable

risk could be made by the people through their

representatives. ”

Summary Comments About Technical

Panels and Study of Their Feasibility

The number of proposals for risk determination panels almost guarantees that the panels

will remain an issue in Federal policy about carcinogens. Establishment of such a panel would

represent a significant change in the process

used by the Federal Government to make decisions about health risks.

Proponents of panels claim they would improve the efficiency of the regulatory process. A

panel would make technical decisions for all the

agencies, which is seen as assuring consistent

scientific findings. Secondly, a time limit imposed on panel deliberations would ensure that

it complete its work quickly. Finally, a regulatory agency could initiate the panel review of

data about a suspect substance, and therefore

the review could take place when it best fits the

agency schedule.

Public interest, labor, environmental organizations, and the Federal regulatory agencies oppose these suggestions. They see regulatory

agencies as the appropriate and lawful locations

for making decisions about risk. In general they

see a science panel as another layer of bureaucracy that might hinder regulatory activities, and

worry that a single panel might be more sensitive to pressure from interested parties. Furthermore, they see the division between “science” and “policy” in decisions about cancer as

illusionary. They argue that such a panel might

have the power to delay decisions by imposing a

higher standard of proof that a substance was a

carcinogen than is required by law. This would

stymie preventive “precautionary” governmental action which they view as necessary to protect lives and health when certainty cannot be

achieved.

Congress has appropriated $500,000 to FDA

to place a contract to investigate the feasibility

of a centralized science panel, and a report is expected in 1982. The results of that study should

answer questions about how the panel might

function and how, or if, scientific and technical

decisions can be made separately from policy or

regulatory decisions. The FDA-sponsored study

may also reveal whether difficulties associated

with chemical regulations have hinged on scientific or on regulatory controversies. If the study

shows that scientific errors have seldom resulted

from processes used by the Government or that

the errors have been of little importance,
changes in the process of making scientific deci- ly, if many examples of incorrect scientific decisions would seem to have little merit. Converse- sions are found, changes might be appropriate.

MAKING REGULATORY DECISIONS

Possible Decisionmaking Frameworks

Each environmental health law seeks to reduce risks to the public health. Lave (204) discusses “frameworks” under which regulatory

decisions can be made, and his categorizations

are the basis for this section. He arrays the

frameworks from that requiring the least information and analysis––the no-risk framework—

to that requiring the most information and

analysis—the benefit-cost framework. Some are

familiar, describing the way in which decisions

are made today; some suggest possible future

directions.

1. The Delaney clause is most frequently mentioned as an example of the no-risk framework. It is a statement that Congress, concerned about the safety of food additives,

has done the balancing of risks and benefits

and has decided no benefits of food additives

can outweigh a demonstrated cancer risk.

FDA, the agency that administers Delaney,

must show a risk before it bans an additive;

it does not have to identify and measure benefits. Even if other organizations identify

and measure benefits, FDA cannot balance

benefits against risk.

2. The risk-risk framework requires a comparison of the risks associated with continued

use of a substance to any risks generated by

its use being controlled or discontinued.

Generated risks would include those inherent in substitutes that might be employed in

place of the substance. The best and most

direct example of risk-risk analysis is the use

of dangerous drugs to treat life threatening

diseases. The risk from use of the drug can

be compared with the risk of death if it is not

used. A regulatory risk-risk determination is

required under section 202 of CAA. As an

example, a control device that reduced particulate emissions might, at the same time,

produce chemical emissions. The risks from

3.

4.

allowing continued particulate emissions

would be compared to the risks from the

chemical emissions.

Direct risk-risk analysis could also have

been applied to nitrites added to food if the

Federal Government had sustained its case

that nitrites were carcinogenic and deserving

of regulation. Eliminating or reducing use of

nitrites as a preservative would have increased the risk of botulism (severe food

poisoning). Its continued use might be associated with a cancer risk. Under the risk-risk

framework, a decision to ban, to reduce use,

or to allow curent use patterns might have

been made by comparing expected deaths

from botulism and from cancer under the

different levels of regulation.

General balancing of risks against benefits

differs from the first two frameworks and

parallels all others in that it allows consideration of effects other than health. Lave

says that the framework is purposefully

loose and vague; it requires enumeration of

all effects, but weighing and balancing them,

as well as deciding which to quantify, is left

to the regulator. He includes determination

of “feasibility” under the OSH Act and regulations of air and water pollution which require BPT and BAT under this framework.

In reality there is no best available technology. It can always be made better, (e.g., by

placing two control devices in series) but at

some point costs are judged to be prohibitive. The hallmark of this framework is balancing of risks and benefits without quantification and analysis. Because of deficiencies

in available and attainable information a

general balancing approach is probably used

in most decisionmaking.

Cost effectiveness compares the costs of different ways to reach the same goal. (The Implications of Cost-Effectiveness Analysis on

Medical Technology (285) discusses this
method and its application to medical practice. ) In general, the framework assumes a

fixed budget and produces an allocation of

resources (money) among different programs which share a common objective.

Programs selected for funding are those that

go farthest toward reaching the goal, in this

case, reduced cancer incidence and mortality, at the least cost.

The expenditure of public funds is required to develop, promulgate, and enforce

regulations. Private funds are expended to

argue against regulations and to buy and

maintain control devices. Cost-effectiveness

techniques can be used to compare the total

cost of a regulation, i.e., agency costs, industry costs, and costs passed onto consumers to the benefits of the regulation.

Alternatively, cost-effectiveness analysis can

compare benefits to either public or private

costs separately.

Regulations that are expected to prevent

the most cancers at the lowest cost would be

identified in a cost-effectiveness framework.

The difficulties of evaluating costs and benefits make it unlikely that the technique can

distinguish between regulations of near

equal benefits and costs, but distinctions

should be possible between the most and

least cost-effective.

Informal discussions with officials at EPA

and OSHA suggest that Government costs

are about the same for every regulation because each regulation is likely to be challenged in court, and each one requires about

the same amount of staff time, whether its

impact is large or small. Although this opinion was commonly expressed, no attempt

was made to verify it. If it is true, an agency

can select its goals by concentrating on those

that will produce the biggest health benefit.

The regulatory budget strategy applies

cost effectiveness to non-Government costs.

Under it each agency might be granted an

amount of private sector costs that its

regulations could generate. Working within

that amount, the agency would then propose

regulations that it intends to promulgate and

submit them for executive approval. This

5.

approach considers only costs to be borne

by the private sector and could set an upper

limit on those costs. OMB (280) reported

that difficulties in estimating such costs

make this approach infeasible.

Benefit-cost or cost-benefit analysis is similar to general balancing of risks against benefits but is more formal and quantitative. In

this framework, all costs and benefits are expressed in dollars, and this analysis requires

placing a monetary value on human life.

After all items under consideration are converted to dollar terms, the benefits and costs

are compared and if the benefits of the regulation exceed the costs, the decision is

weighted toward making the regulation.

Placing a dollar value on human life is one of

the most controversial aspects of this method, and it is simply repugnant to many people.

Lave claims the benefits of this framework

are that it is the most flexible, requires the

most information and analysis, and drives

qualification where possible. Formal benefitcost analysis is not now required by any carcinogen regulating law, but it is required by

Executive Order No. 12291 where legislation

does not forbid it, and it is frequently mentioned in plans for regulatory reform. A

hearing of the Subcommittee on Oversight

and Investigations (334) of the then House

Committee on Interstate and Foreign Commerce provides a juxtaposition of opposing

views of the applicability of the technique to

regulatory decisionmaking.

Feasibility and Limits of

Benefit-Cost Analysis

Traditional benefit-cost analysis is an economic tool that requires listing of all benefits

and costs and assigning a dollar value to each.

Carcinogen regulations involve the ultimate

considerations—life and death—and opinions

differ about whether or not a monetary value

can be placed on life. In what ever way that

controversy is settled, certain comments can be

made about the usefulness of benefit-cost

analysis.
198 ● Technologies for Determining Cancer Risks From the Environment

In the case of a carcinogen regulation, expected benefits include the health gains from

reducing exposure to the agent, and uncertainty

is attached to the circulation of these gains.

Presenting the expected health gain as a number

does not add certainty to the estimate, but it

adds to the estimate’s importance. A frequent

observation is that caveats and reservations attached to the numbers in the analysis are lost.

The number of premature deaths to be averted

(“lives saved”) as well as the number of dollars

to be spent to achieve the benefit take on lives of

their own and are unencumbered by statistical

reservations about accuracy. In this way, with

no more information behind them, the numbers

become more certain in the public’s and the decisionmakers’ minds. Too much reliance on imprecise numbers becomes a special problem in

benefit-cost analysis which reduces the benefits

and costs to dollar figures. This problem is commonly acknowledged but a practical solution is

not readily apparent.

Many criticisms are directed at benefit-cost

analysis. Lave (204) claims that a well-done

analysis will always favor the status quo;

change costs money. Change can be produced

by going either from regulation to no regulation

or from no regulation to regulation. Lave goes

on to say that it would be surprising if the present state is truly the pinnacle of social evolution.

If such a tilt toward the status quo exists when

all measurements and calculations are accurately done, it is easy to imagine how a bias on the

part of the analyst could affect the analysis. Not

all economists agree with Lave’s statement that

benefit-cost analysis will always favor the status

quo, and Freeman (132) cites the NAS 1974

study, Air Quality and Automobile Emissions

Control, as an example of cost-benefit analysis

which favored tighter controls.

Two other criticisms are directed at benefitcost analysis. Equity considerations are not a

part of benefit-cost analysis. For instance, the

health benefits from a regulation accrue to those

individuals whose risks are decreased; the cost

of reducing the risks is borne by those who pay

for the control devices or procedure. However,

the situation before the control is implemented

has the exposed people bearing a health risk

which spares anyone in society from having to

pay to reduce the exposure. The technique of

cost-benefit analysis is silent about whether

either case is just.

Another difficulty encountered with benefitcost analysis is its inability to consider intergenerational effects. As a specific example,

many substances are both carcinogens and

mutagens. Such a substance may cause cancer in

people exposed to it and mutations in their germ

cells. The mutations are expressed in the next

generation. Quantifying genetic damage is at

least as difficult as expressing the value of a life

in dollars.

A quite different problem in dealing with the

future is economic. The discount rate chosen to

project monetary costs and benefits is very important to these analyses, but there is no agreement about the appropriate rate, especially in

inflationary times.

A response to objections about valuing lives

in dollar terms is seen in the suggestion of the

Conservation Foundation (78) that different

types of analyses can be carried out under the

benefit-cost rubric. It suggests use of the term

“single-value analysis” to describe benefit-cost

analyses which express all items in dollar terms

and “two-value analysis” for analysis that compare “lives saved” to “dollars cost. ”

The Conservation Foundation found “twovalue” analysis appropriate for carcinogens

when the major concern is death. It is less easily

applied when additional considerations, such as

damage to an ecosystem, are involved. “Multivalue analysis” is suggested as a method to consider three or more irreducible elements. It enables tradeoffs to be made, e.g., human health

risk v. costs of reducing exposure, and ecosystem risk v. costs, but the analysis becomes

more difficult. The claimed advantage of benefit-cost analysis (that it forces a detailing of

what is being considered) is equally applicable

to the one-, two-, and multi-value methods. The

two- and multi-value methods involve balancing of health risk against other factors, and fit

within Lave’s third framework of general balancing of risks and benefits.
While two-value or multivalue benefit cost

analysis may be attractive because of its rigor

and its not placing a dollar value on life, it is

not, strictly speaking, benefit-cost analysis. A

benefit-cost analysis drives toward a single

number, the quotient obtained when benefits

are divided by costs. If the quotient exceeds 1.0,

the benefits are greater than the costs, and the

project should, on an economic basis, proceed.

If it is less than 1.0 it should not. Two-value and

multivalue benefit-cost analyses produce no

such quotient. Instead they compare the benefits

in one term (i. e., lives) v. costs (in dollars). The

comparison is useful in a cost-effectiveness approach, where various approaches to a common

goal can be ranked, but it does not produce a

number that indicates “yes” or “no. ”

A working

Principles of

Chemicals in

that:

panel of the NAS Committee on

Decision Making for Regulating

the Environment (263) concluded

The systematic application of the tools of

decision analysis and benefit-cost analysis can

provide the decision maker with a useful framework and language for describing and discussing

trade-offs, noncommensurability, and uncertainty. This framework should help to clarify

the existence of alternatives, decision points,

gaps in information, and value judgments concerning trade-offs.

Decision analysis, as described in the NAS report, is a careful detailing of regulatory options,

expected outcomes and uncertainties of risks,

benefits, and costs. Its “main contribution . . .

is to organize information for the decisionmaker

to assist him in his unavoidable balancing task. ”

The NRC committee (263) endorsed the use of

benefit-cost analysis and concluded that the

technique is useful in making decisions, but that

it should not be the only consideration in the

decision. Furthermore it did not recommend

continued research to improve the techniques

because “highly formalized methods of benefitcost analysis can seldom be used for making

decisions about regulating chemicals in the

environment. ”

If market prices and shadow prices are fully

utilized to value economic efficiency effects, the

initial list of noncommensurate effects of the

decision will have been reduced to:

 fully commensurate economic efficiency benefits and costs measured in dollars; and

● noncommensurate effects, described and

quantified in other units, of which the most

significant are likely to be hazards to health

and life, damages to the environment and

ecosystems, and the distribution of benefits,

costs, and hazards among individuals and

groups.

The NRC definition of benefit-cost analysis does

not require that all costs and benefits be expressed in a common unit (dollars), and it too

would fit in Lave’s third framework.

This assessment, which deals with the science

and policy of making decisions about carcinogens, has emphasized uncertainties in determining risk. The Conservation Foundation (78) and

NRC (263) also draw attention to uncertainties

in projecting costs of regulations. Both sides of

the benefit-cost analysis are difficult, subject to

human error, and encumbered by uncertainties.

Nevertheless, this method, whether one-, or

two- or multi-value has its advocates, and it is

increasingly mentioned as at least a tool to be

used by decisionmakers.

An Alternative to Benefit-Cost Analysis

for Making Regulatory Decisions

Sometimes the world seems divided between

economists and lawyers. Economists favor decision frameworks that rely on quantitation and,

in benefit-cost approaches, on converting all

values into dollars. Lawyers are more comfortable with qualitative concepts as developed

on a case-by-case basis under common law. In

making decisions about risks under common

law, courts rely on concepts of reasonableness

of behavior, of duties and responsibilities to

learn and to inform, of assumptions of risk that

are made by different parties, and of contributory behavior. Application of these concepts is constrained by common law precedents,

procedural rules, and rules about admissibility

of competent evidence. Quantitative considerations of costs and benefits play a minor role

(20).
Regulatory law differs from the common law.

Its history is shorter, and it is constrained and

governed by many specific and varied enabling

statutes, the Administrative Procedures Act, the

Regulatory Flexibility Act, and Executive Order

12291. However, more importantly, the

regulatory agencies rely heavily on semiquantitative and quantitative risk assessment techniques, on experts, and, increasingly on a benefitcost framework for decisionmaking. Agency

emphasis on quantitation, which “invites . . . playing with the numbers” to reach

certain analytical outcomes is producing a “lack

of credibility or acceptance in the public and the

regulated industries” according to Baram (20).

Offered against these criticisms of benefit-cost

analysis are “the rational approach to decisionmaking that it allegedly fosters” and that “it emphasizes economic considerations, it retards excessively zealous regulations, it ensures that in

general only incremental controls will be promulgated. ”

This has now become the central controversy

for the regulatory agencies: How to implement

their mandates to control carcinogenic risk in a

fair, objective and accountable manner by using

a “rational” framework (e.g., cost-benefit)

which emphasizes economic cost factors, when

the health and environmental benefits at stake

are generally considered as being unmeasurable

in economic terms (20).

Baram offers a decision framework that considers costs, but which also relies on qualitative

considerations for regulatory agency consideration. His framework has six steps. The first two

are common to any such decisionmaking

scheme—hazard identification and risk measurement—but beyond those steps, he considers

risk management options that he says are now

overlooked.

1. Hazard identification, —This step involves

the technologies discussed in this report and

is initiated when a test shows a substance is a

carcinogen. The development of the initial

finding of hazard can be accomplished by

Government or non-Government testing,

because of a governmental rule requiring a

test by private industry, or by presentation

of a petition for rulemaking to an agency.

2.

3.

4.

Risk measurement. --This step, too, involves some technologies discussed here.

Baram emphasizes that agencies can improve their performance at this step.

Since agencies can use evidence in their

rulemaking which would not be considered

competent for admission in a trial in court,

there are few legal protocols governing the

quality of the evidence . . . [used] . . . in

rulemaking. Clearly, there is a need for the

agencies to establish such admissibility of

evidence protocols and to bind themselves

to the protocols if the competency and probative quality of the evidence used is to be

improved and the confidence of the public

and regulates in agency findings is to be increased. Costs will be a major factor in establishing such protocols . . . . Thus, it is

imperative that agencies jointly address how

to manage their resources for risk measurement collectively in the most efficient manner, and to establish collectively the costs to

be imposed on industry for risk measurement when the measurement task is mandated for industry by law (20).

Risk management options selection. — This

step is absent from current regulatory programs. It would identify and roughly assess

the efficacy of regulatory and nonregulatory

approaches to risk management. Regulatory

options include both a) setting new standards and b) enforcing in-place standards.

Nonregulatory approaches include a) recourse to common law, b) voluntary industrial standard setting, c) restrictions on future Federal procurement from sources of

risk, and d) education or public disclosure

programs.

Economic and technical feasibilit y analyses.—These analyses are required by some

enabling statutes, Executive Order No.

12291, and the Regulatory Flexibility Act.

They would focus on the management options identified in step 3.

The second, third, and fourth stages of

measuring risk, assessing options, and

costing options should ideally be kept

separate and independent to ensure that risk

measurement and option identification results are objectively arrived at on the basis

of the best data and analytic methods for
Ch. 6—Approaches to Regulating Carcinogens ● 201

risk estimation. This accords with the findings of many critics of the regulatory management of risk who have found a breakdown in risk measurement objectivity when

it is influenced by cost considerations. This

important reform need not be Congressionally mandated, but can be accomplished

by the responsible exercise of agency discretion under existing statutes. It permits each

agency then to conduct its fourth stage of

economic and technical analysis in a structured fashion—as cost-effectiveness analyses

of each option separately and in certain

combinations (20).

5. Ordering of risk management initiatives. —

Having identified and measured risks and

selected the most efficacious and costeffective management options which are

technically feasible, each agency separately

(and in conjunction if several find the same

carcinogen falling within their regulatory

jurisdiction) should then . . . [order] . . .

risks it will choose to manage on the basis of

the carcinogenic risk reduction benefits to be

achieved.

For instance, EPA might decide that the benefits of managing the carcinogenic risks of

asbestos alone far outweigh the benefits of

managing the risks of many chemical substances, and thereby would be in a position

to allot rationally a proportionate amount

of its resources to asbestos (20).

6. Deployment of risk management options—

regulatory and nonregulatory—for selected

priority chemicals. —

Finally, an agency is at the point where it

can proceed to engage in rulemaking and

other regulatory efforts, and foster the use

of available alternatives to regulation, for

reducing the risks from exposure to the selected priority chemicals. The use of alternatives in conjunction with regulation can

be particularly appropriate in those cases

where the number of exposed persons is relatively small (as determined in step 2); the

alternatives are promising in terms of their

efficacy for reducing the risk (as determined

in step 3); regulatory approaches do not appear to be cost-effective or technically feasible (as determined in step 4); or the agency

has determined that an optional allocation

of its resources on the basis of its selected

priority chemicals militates against promulgating and enforcing regulations (as determined in step 5). Thus, although the rational approach to risk management precludes regulating such chemicals, the agency

assumes the continuing responsibility of

fostering alternative approaches to manage

such risks in keeping with societal values

which support the protection of individuals

from the dangerous acts of others. Following

these actions, the agency has the responsibility to monitor results and take necessary

corrective steps—e. g., in the case when the

use of alternatives has failed, the agency

may renew its efforts to foster the use of

alternatives or decide to regulate (20).

Agencies can adopt either this specific risk

management approach or some other approach,

without congressional intervention or mandate.

Baram proposes that agencies publish two rules

to govern their use of the framework in order to

guard against ad hoc or case-by-case subjective

determinations. The first would describe the

procedures it will follow; the second, any agency assumptions about subjective elements of its

analyses.

This scheme shares drawbacks with any that

involves ordering of regulatory goals. The decision that a risk is number one may be challenged, and concern about the accuracy with

which the actual number one is identified may

prolong the ordering process. Also, the publication of a number one risk, say, asbestos in step 5

above, might be accompanied with a list of

“also-rans.” Whether such risks would go unchecked because it is clear that agency resources

would never reach them or whether voluntary

risk reductions would flow from the publication

is a ponderable question.

Baram’s step 3 may be the most critical difference between what is now done and what

might be done. Considering alternatives, discussing and comparing them, would better ensure the public and the regulated industry that

the most efficacious approach was being selected. It also incorporates the cost-effectiveness

framework to choose between alternatives. The

scheme enjoys a powerful attractiveness in that

it considers nonregulatory management of risks

while reserving the regulatory “club” if it is

necessary.
202 Technologies for Determining Cancer Risks From the Environment

Making an Unreasonable Risk Decision

“Unreasonable risk, ” the operational term in

TSCA and CPSA, was of special interest to this

assessment. It is a balancing term, and Congress

decided not to define it, either in the laws or in

the legislative history.

The House version of CPSA attempted a definition of “unreasonable risk” which involved

comparing the severity and frequency of potential injury to the utility of the product, but the

definition was deleted in the conference committee (145). In TSCA, the term was left undefined

to allow maximum latitude to the EPA Administrator in making decisions. However, the House

Interstate and Foreign Commerce Committee report accompanying TSCA states that unreasonable risk determinations involve (65):

. . . balancing the probabilities that harm will

occur and the magnitude and severity of that

harm against the effect of proposed regulatory

action on the availability to society of the

benefits of the substance or mixture, taking into

account the availability of substitutes for the

substance or mixture which do not require regulation, and other adverse effects which such

proposed action may have on society.

OTA undertook two efforts to learn about the

term “unreasonable risk” and how it might be

applied in regulatory efforts. The first effort was

a letter of inquiry to knowledgeable people and

the second was a workshop held by the New

York Academy of Sciences. They are described

in appendix B.

Some responses to the letter viewed any risk

of cancer as unreasonable in itself. Other respondents favored balancing the risk of cancer

against benefits of the substance in question.

These two groups 01 responses parallel two approaches to regulatory law that were discussed

earlier. Another suggestion was that consumers

should make their own unreasonable risk decision about consumer products. The Government would tell them of the risk; they would

decide whether or not to accept the risk.

The same division between risk-based and

balancing approaches to regulating carcinogens

was reflected in discussions at the workshop.

The workshop heard a number of talks and discussions favoring cost effectiveness as a method

for deciding on regulatory approaches.

Unreasonable risk has been used as the basis

of regulatory action in a limited number of

cases. To date, EPA has promulgated three regulations under TSCA to limit unreasonable risks

from substances in the environment. TSCA required that EPA regulate PCBs; EPA regulated

fully halogenated chlorofluoroalkanes, which

threaten the ozone layer in the atmosphere, and

it prohibited a company from disposing of

2,3,7,8-tetrachlorodibenzo-para-dioxin (“dioxin”) at a particular facility. The few regulatory

actions so far undertaken do not provide a coherent picture of how EPA will make unreasonable risk decisions. It is noteworthy that each of

these actions dealt with a substance associated

with cancer.

In response to a General Accounting Office

(141) report, EPA stated that it had not developed “decision criteria” to make unreasonable risk decisions in the course of premanufacture review under section 5 of TSCA. The

agency has considered drawing up such criteria,

but found that the amount and variety of in formation to be weighed in such decisions precluded their developing criteria. Premanufacturing notices (PMNs) (see ch. 4) are considered

on a case-by-case basis, and EPA considers that

approach satisfactory at this time.

EPA assembles health and economic data

about a substance considered for regulation

and, in different offices, carries out a risk assessment and an economic assessment. These two

assessments are then used to reach a decision

about unreasonable risk. EPA guidelines (101)

for making judgments about carcinogenicity,

govern risk assessments. EPA has not yet published information about how it will carry out

economic assessments (20). Each assessment

carries with it some uncertainties and the quality of the data that go into the assessments

varies, but eventually the results of the assessments go to the Administrator (78):

The last stages of determining unreasonable

risk (under TSCA) involve the Administrator of

EPA, the Assistant Administrator for Toxic Substances, and perhaps one or two other high-level
Ch. 6—Approaches to Regulating Carcinogens ● 203

officials evaluating the evidence and analysis,

sorting through their own personal values, perhaps testing the political winds, and then coming

to a conclusion. It is definitely not a process that

can be subjected to tidy rules or guidelines.

The Administrator, who is appointed by the

President, makes and publishes the decision. He

is responsible for the decision made, and if it is

shown to be incorrect, he can be removed from

his position.

Not “Unreasonable Risks” and

What To Do About Them

It seems likely that testing of chemicals will

reveal a substantial number that present

“limited” but not “sufficient” evidence for carcinogenicity. The words “limited” and “sufficient”

are borrowed from the International Agency for

Research on Cancer’s (IARC) classification (see

ch. 4 and app. A). In the case of “limited,” the

available evidence supports the idea that the

substance is a carcinogen, but it is less than “sufficient” to force a conclusion.

A regulator might consider a substance for

which only “limited” evidence exists as deserving of regulation. He might come to this decision because many people or very sensitive people, such as young children, were exposed or

because a substitute was readily available.

Whatever his reasons for considering regulation, economic assessment of most chemicals in

commerce will probably show that significant

costs would attend any regulatory scheme. In

other words, often there may be a small risk and

large costs. With those assessment results, it is

likely that further analysis will not result in an

answer that says “regulate” under the formal,

rigorous balancing mechanisms discussed here.

A regulator who sees his first responsibility to

be the protection of public health might be uncomfortable with that decision, and the producer of the substance, although not wanting to

be regulated, might be uncomfortable also with

continuing exposure at current levels. Methods

to deal with these situations through discussion

and incentives might reduce the antagonism between regulators and the private sector and promote public health (19, 20).

RESPONSIBILITY FOR MAKING DECISIONS

Quantification of risks and benefits is never

likely to be so precise that estimates of these

variables can be plugged into a formula to produce a number that dictates a decision. Instead,

after all the analyses, a decision about whether a

risk is acceptable or unacceptable and reasonable or unreasonable will be made by a few

individuals. Those judgments reflect societal

values and would, ideally, be made by citizens

as a whole. In our form of Government, elected

representatives are responsible for expressing

societal values, and this responsibility is sometimes delegated by elected representatives to executive or judicial branch officials.

Executive Branch Decisions

The size and complexities of Government

have resulted in elected representatives delegating authority to make judgments about

acceptable risk to executive branch agencies. A

number of commentors, including Markey

(222), point out that many executive branch officials are civil servants with almost lifetime

tenure. While high-level appointees, such as the

EPA Administrator, are at some risk if they

make poor decisions, tenured civil servants are

not. Citizens who feel aggrieved as a result of

executive branch decisions have little opportunity for redress (222).

Field (120) cites a number of legal scholars

who contend that “vague mandates” such as

TSCA’s directions to reduce or eliminate “unreasonable risks” give too much discretion to

agencies:

If regulatory decisions are to be broadly acceptable, the governing statutes must do more
204 ● Technologies for Determining Cancer Risks From the Environment

than provide for decisions about what is safe or

what is an unreasonable risk. They must also do

more than merely list factors to be considered.

The legislative process must make the basic

value judgments and tell the agencies how to

make the necessary trade-offs. . . .

Insofar as statutes do not effectively dictate

agency actions, individual autonomy is vulnerable to the imposition of sanctions at the unruled

will of executive officials, major questions of

social and economic policy are determined by

officials who are not formally accountable to the

electorate, and both the checking and validating

functions of the traditional model are impaired

(120).

Baram (19) draws attention to the frequent

absence of confessional direction about what

factors agencies are to consider in reducing risk.

Absence of that direction, he says, causes the

agencies to face extensive litigation.

Judiciary Branch Decisions

Markey (222) expresses concern about the

judiciary becoming too involved in making

decisions about acceptable risk. He sees such

decisions as best made in the political arena by

officials responsible to the electorate. Judges, he

points out, often enjoy lifetime tenure and are

more removed from the electoral process than

are executive branch officials.

Vague definitions such as “unreasonable risk”

that occur in the balancing laws are seen as inviting legal challenge and judicial involvement

in risk decisions. The courts have generally

given great weight to “agency procedural safeguards, substantiality of evidence, and consistency” (120), but two recent developments

may alter such preference. As discussed above,

the Bumpers amendment would erase the judicial preference shown to agency expertise, and

the courts would entertain challenges to agency

expertise. Judicial involvement is also increased

because of industry challenges to agency rules

and consumer, environmental, and labor organization challenges to agencies for not regulating. Whatever the source of challenge, judicial reviews have an impact on what level of risk

will be acceptable. Should a court modify an

agency-decided risk level, it is reasonable to

assume that the agency, in making its next decision, will consider the courts’ decree.

Directions From Congress

Congressional attention to details about what

to balance and how to balance are seen as solutions to some of the problems of the regulatory

agencies. Interestingly, regulatory agency attorneys interviewed by Field (120) generally

favored balancing laws. They see their agencies

well able to do an adequate job of balancing

risks and benefits and evidently do not share the

concerns about vague mandates.

Attorneys for four environmental interest

groups were also interviewed (120). Three were

opposed to balancing laws and favored that the

Congress impose clearer mandates for regulatory action. Vague, balancing laws were seen as

favoring industry because of its greater resources for influencing decisions in the agencies

and in the courts. The fourth environmental attorney suggested that lack of money hampered

public interest group representation and that

Federal funding for preparation of their cases

would ease their difficulties.

Clearly, different laws impose different standards, and the balancing laws are not specific

about what is to be balanced. Litigation results

from these characteristics of the laws. Congressional intervention to define standards and

to detail what to balance should reduce litigation from those sources.

However, there is no guarantee that clearer

directions from Congress will eliminate litigation—e.g., FDA’s banning of the artificial

sweetener, cyclamate, begun in 1969, was contested until 1980 (and may be reopened). Of all

the carcinogen laws, the Delaney clause, which

was the basis of the cyclamate ban, provides the

clearest definition of a carcinogen, and it is the

simplest in the sense that it allows no balancing.

Nevertheless, administrative law hearings contesting the quality of the evidence about carcinogenicity were held off-and-on for a decade.

The FDA decision was upheld.

.

Congress cannot engage in the day-to-day

business of agencies; it does not have the time. It
C/I. 6—Approaches to Regulating Carcinogens 205

must delegate authority to the agencies. If it agencies that no preventive regulatory action is

shares the opinions of some observers that it possible. On the other hand, Congress cannot

does not Provide sufficient direction to the agen- intervene too often in regulatory matters with-

.

cies about acceptable risk and balancing, it out hobbling

might provide the direction or it might more issues.

often exercise its right to intervene in regulatory Regulations activities. some and too

its capacity to deal with other

are seen as too burdensome by

weak by others, but the regulaSome risks are inherent in either remedy. tions are required by law. The laws are congresOverly strict directions, which provide many sional expressions that public policy requires a

points for judicial review might so encumber the certain level of protection for public health.

REGULATED CARCINOGENS

Table 38 lists 102 substances and categories of

substances regulated under the laws discussed

above. In every case, some evidence existed to

indicate that the substance is a carcinogen. In

many cases, evidence about the substance was

generated in the NCI bioassay program (146)

and/or evaluated by IARC (185,186). The lefthand columns of the table describe what conclusions were drawn about the human and animal

substances by NCI and IARC.

IARC has classified 18 substances or processes as human carcinogens and another 18 as

probable human carcinogens. The data in table

38 show that 20 of those chemicals are regulated. Each of those 20 is identified by a “C,”

carcinogen or “PC” probable carcinogen, in the

“H,” human evidence, column under IARC.

About one-third of the chemicals tested by

NCI or reviewed by IARC present “sufficient”

evidence to conclude that they are carcinogens

in animals and they can therefore be assumed to

present a carcinogenic risk for humans (see,

e.g., 185). Chemicals from those classes are indicated with an “S” on the table in the “A,”

animal evidence, column; the “I” classification

means the available evidence is limited but

presents a strong warning of carcinogenicity.

About half of the chemicals reviewed by

IARC and/or tested by NCI presented neither

sufficient nor limited evidence of carcinogenicity. Only one chemical for which there is only inadequate (I) evidence of carcinogenicity appears

in table 38. It is not possible to decide from the

data in the table that risky chemicals are being

regulated at the proper pace, but the data do

lead to the conclusion that nonrisky chemicals

(as judged by IARC and NCI) are not often regulated. The conclusion then suggests that regulations are not so haphazardly drawn as to regulate large numbers of chemicals that present no

or very little risk.

The absence of an entry under “NCI” or

“IARC” does not necessarily mean that there is

poor or limited evidence about carcinogenicity.

For instance, although the first substance, 2-acetylaminofluorene, does not occur on either the

NCI or the IARC list, it is an accepted animal

carcinogen (see ch. 5). Furthermore, other

chemicals have been reviewed since the IARC

(186) publication, but the results of the reviews

are not yet available.

Some complexities of regulating carcinogens

are demonstrated by the table. Some substances

present a risk in locations covered by different

laws, and separate regulations are necessary for

each exposure. Under CAA, EPA has proposed

regulation for, or regulated, 6 carcinogens and

is considering an additional 24. Section 311 of

CWA deals with oil and hazardous spills, and is

not focused on regulating carcinogens, but “hazardous discharge reporting levels” have been

promulgated for the listed chemicals, and carcinogenicity was considered in setting those

levels. The 49 substances for which regulation is

required under section 307 of CWA were included in the law in 1977. Standards have been set

for trihalomethanes, including chloroform,

under the Safe Drinking Water Act. A few
206 ● Technologies for Determining Cancer Risks From the Environment

Table 38.-Substances Regulated as Carcinogens Under Various Acts

Evaluation by Statutes

NCI IARC CWA CWA

A H A Chemical CAA $307 $311 SDWA FIFRA OSHA FDCA CPSA

— 2-acetylaminofluorene (2-AAF) OSHA

—

L—

r ——

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

s—

—

s

I —

—

—

—

—

—

—

—

—

—

—

(s)

—

—

—

Pc

Pc

z

z

:

—

:

—

—

Pc

Pc

E

Pc

I

I

I —

c

c

—

—

—

—

—

—

—

—

—

—

—

I —

—

—

—

—

i

c

—

—

—

—

—

I —

Pc

—

—

—

—

—

—

—

;

s

;

s

I

i

s

A

s

:

s

L

s

:

s

L

L

s

s

s

s

N

N

N

N

N

N

N

N

N

N

N

:

s

N

s

s

L

N

s

:

s

N

L

L

N

I

N

N

N

N

L

s

N

Acrylonitrile

Aflatoxin

Aldrin

4-aminobiphenyl

Aramite

Arsenic

Arsenic compounds

Asbestos

Benz(a)anthracene

Benzene

Benzidine

Benzo(b)fluoranthene

Benzo(a)pyrene

Beryllium

Beryllium compounds

Bis(2-chloroethyl)ether (BCEE)

Bis(chloromethyl)ether (BCME)

Cadmium

Cadmium compounds

Carbon tetrachloride

Chlordane

Chlorobenzilate

Chloroform (a trihalomethane, THM)

Chloromethyl ether

Chromium compounds (hexavalent)

Coal tar and soot

Coke oven emissions (polycyclic

organic matter; “POM”)

Creosote

Cyclamates

D&C Blue No. 6

D&C Red No. 10

D&C Red No. 11

D&C Red No. 12

D&C Red No. 13

D&C Yellow No. 1

D&C Yellow No. 9

D&C Yellow No. 10

DDT (dichlorodiphenyltrichloroethane)

Dibenz(a,h)anthracene

1,2-dibromo-3-chloropropane

1,2 dibromoethane

3,3’ -dichlorobenzidine

1,2-dichloroethane

Dieldrin

Diethyipyrocarbonate

Diethylstilbestrol (DES)

4-dimethylaminoazobenzene

2,4-dinitrotoluene

1,4-dioxane

1,2-diphenylhydrazine

Dulcin

Epichlorohydrin

Ethylene bis dithiocarbamate

Ethylene oxide

FD&C Red No. 2

FD&C Violet No. 1

Formaldehyde

Graphite

Heptachlor

Hexachlorobenzene

Hexachlorobutadiene

RR

—

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

RR

—

RR

—

RR

—

—

—

—

—

—

—

—

—

—

—

RR

RR

—

—

RR

RR

RR

—

—

—

RR

—

RR

—

—

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—

—

—

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—

RR

RR

RR

—

L

—

L

—

—

—

L

—

—

L

—

—

—

L

L

—

L

L

L

—

L

—

L

—

—

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—

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—

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—

—

—

L

—

—

L

L

L

—

—

—

L

—

L

—

L

—

—

—

—

L

—

L

L

L

—

—

—

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—

—

R

a

—

—

—

—

—

—

—

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—

—

—

R

a

—

—

—

—

R

—

—

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—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

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—

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—

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—

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—

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—

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—

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—

—

—

v—

v—

v

R

R

—

—

—

—

—

—

—

—

—

—

R

R

—

R

R

—

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—

R

—

—

—

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—

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—

—

—

R

—

R

a

R

—

—

R

—

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—

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—

—

—

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R

R

—

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—

—

R

—

—

R

—

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—

R

—

R

a

.—

R

R

—

—

. -

—

R

—

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R

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—

R

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—

—

—

R

—

R

—

—

—

—

R

—

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—

—

—

—

—

—

—

—

—

—

—

—

—

—

R

—

—

—

—

—

—

—

—

—

—

—

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—

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—

—

—

—

R

R

R

R

R

R

R

:

—

—

—

—

—

—

—

R

R

—

—

—

—

R

—

—

—

R

R

i

—

—

—

—

—

—

—

—

—

—

i—

R

R

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

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—

—

—

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—

—

—

—

—

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—

—

—

—

—

—

—

—

—
Table 38.–Substances Regulated as Carcinogens Under Various Acts (Continued)

Evaluation by Statutes

NCI I ARC CWA CWA

Al- f A Chemical CAA $307 $311 SDWA FIFRA OSHA FDCA

—

—

—

(s)

s—

—

—

—

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(s)

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N

N

N

s

s

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N

s

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s

s

s

s

N

N

N

s

s

s

N

N

N

:

N

L

N

N

N

s

N

—

Hexachlorocyclohexane

a-hexachlorocyclohexane

@hexachlorocyclohexane

Hexachloroethane

Ideno(1 ,2,3-cd) pyrene

Kepone (chlordecone)

Lindane

Mercaptoimidazoline

4,4’ methylene bis (2-chloroaniline)

a-naphthylamine

2-naphthylamine

Nickel

Nickel compounds

Nitrosamines

4-nitrobiphenyl

N-nitrosodi-n-butylamine

N-nitrosodiethylamine (DENA)

N-nitrosodimethylamine (DMNA)

N-nitrosodi-n-propylamine

N-nitroso-N-ethylurea (NEU)

N-riitroso-N-methylurea (N MU)

Oil of calamus

P-4000

Pentachloronitrobenzene(PCNB)

Polychlorinated biphenyls (PCBs;

Toxic Substances Control Act-RR)

p-propiolactone

Safrole

2,3,7,8 -tetrachlorodibenzo-p-dioxin

(TCDD, “dioxin”)

1,1 ,2,2 -tetrachlorethane

Tetrachloroethylene

(perchloroethylene)

Thiourea

Toxaphene

1,1 ,2-trichloroethane

Trichloroethylene

2,4,6-trichlorophenol

Trihalomethanes (THM)

“Tris” (flame retardant)

Vinyl chloride

Vinylidene chloride

Radionuclides

—

—

—

—

—

—

—

—

—

—

c

c—

—

—

—

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;

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RR

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RR

RR

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L

L

L

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L

L

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L

L

L

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L

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L

L

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L

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R

a

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—

—

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—

R

a

—

—

—

R—

—

—

—

—

—

—

—

—

v

R

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

R

—

—

v

—

—

—

—

R

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

R

R

R

—

—

—

R

—

—

R

—

—

—

—

—

—

—

R

—

—

—

—

—

—

—

—

—

—

k

—

—

—

—

—

—

—

—

—

R

R

—

—

—

—

R

—

—

—

—

—

—

—

R

R

—

R

—

R

—

—

—

R

—

—

—

—

—

—

—

—

—

Abbreviations

NCI National Cancer Institute data (146)

IARC International Agency for Research on Cancer evaluation (185. 186)

A = animal evide”nce

S = sufficient evidence for carcinogenicity (for more description see Chapter 4, Appendix A)

(S) = Class 3 of NCI; very strong evidence is 1 species; no evidence in 2nd species

L = limited evidence for carcinogenicity

I = inadequate evidence for carcinogenicity

H = human evidence

C = identified as a carcinogen from human studies

PC = identified as a probable carcinogen from human studies

I = inadequate evidence to reach a conclusion about carcinogenicitY from human studies

N = not evaluated

CAA

CWA 307

CWA 311

SDWA

FIFRA

OSHA

FDCA

CPSA

Clean Air Act C = being considered for regulation

Clean Water Act &307 P = regulation proposed

Clean Water Act 31 1 R = regulated

Safe Drinking Water Act RR = regulation required by Act

Federal Insecticide, Fungicide, and Rodenticide Act L = discharge levels restricted

Occupational Safety and Health Act v = voluntarily withdrawn from market

Food, Drug, and Cosmetic Act

Consumer Product Safety Act

CPSA

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

R

R

—

—

aRegulation based on non.carcinogenic toxicity (in addition to those indicated, many other listed substances encountered in the workplace are regulated because of

toxicities other than carcinogenicity).
.

208 ● Technologies for Determining Cancer Risks From the Environment

metals and pesticides which are identified as carcinogens are regulated under the same act but

because of other toxic properties. Implementation of FIFRA has resulted in voluntary withdrawal of pesticides before regulations were

promulgated as well as regulations restricting or

forbidding use.

OSHA has regulated the substances shown

because of carcinogenicity and many other substances on the list are regulated in the workplace

because of other toxicities. FDA regulation of

carcinogenic food additives and colors has eliminated most of the listed colors and sweeteners

from the food supply. The Consumer Product

Safety Commission has regulated five chemicals

and benzidine-containing dyes.

The table does not discriminate between regulations that set a permissible limit, such as the

OSHA standards, and those that ban a substance, such as FDA regulations of food colors.

The entry “R” indicates only that some regulation is in effect.

The laws are designed to reduce exposure to

carcinogens. They may regulate too many or

too few chemicals, but chemicals are being regulated. Furthermore, apparently, few nonrisky

chemicals have been regulated under the current

system.
I

Appendixes

.

.
Contents

Page

Appendix A: A Comparison of the National Cancer Institute’s and the

International Agency for Research on Cancer’s Evaluation of

Bioassay Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .211

Appendix B: “Unreasonable Risk” . . . . . . . . . . . . . . . . . . . . . ............215

Appendix C: Abbreviations and Glossary . . . . . . . . . . . . . . . . . . . . . ......221
Appendix Am—A Comparison of the National Cancer

Institute’s and the International Agency for Research

on Cancer’s Evaluation of Bioassay Results

A working group assembled by the International

Agency for Research on Cancer (IARC) reevaluated

data about 354 chemicals previously evaluated and

described in the first 20 IARC monographs (185,186).

The working group developed the following criteria

for grading evidence about carcinogenicity. The first

three categories are essentially the same as those used

in earlier IARC compilations (344), and two new

categories were added:

Sufficient evidence of carcinogenicity indicates that

there is an increased incidence of malignant tumours:

(a) in multiple species or strains; (b) in multiple experiments (preferably with different routes of administration or using different dose levels); (c) to an unusual

degree with regard to incidence, site or type of

tumour, or age at onset. Additional evidence may be

provided by data concerning dose-response effects, as

well as information on mutagenicity or chemical

structure.

Limited evidence of carcinogenicity means that the

data suggest a carcinogenic effect but are limited

because: (a) the studies involve a single species, strain,

or experiment, or (b) the experiments are restricted by

inadequate dosage levels, inadequate duration of exposure to the agent, inadequate period of follow-up,

poor survival, too few animals, or inadequate reporting, or (c) the neoplasms produced often occur spontaneously or are difficult to classify as malignant by

histological criteria alone (e.g., lung and liver tumours in mice).

Inadequate evidence indicates that because of major

qualitative or quantitative limitations, the studies cannot be interpreted as showing either the presence or

absence of a carcinogenic effect.

Negative evidence means that within the limits of

the tests used, the chemical is not carcinogenic. The

number of negative studies is small, since in general,

studies that show no effect are less likely to be published than those suggesting carcinogenicity.

No data indicates that data were not available to

the working group (185).

IARC (185) made the following statement about

the value of bioassay results:

. . . in the absence of adequate data in humans it is

reasonable, for practical purposes, to regard chemicals for which there is sufficient evidence of carcinogenicity (i. e., a causal association) in animals as if

they presented a carcinogenic risk for humans. T h e

use of the expressions “for practical purposes” and “as

if they presented a carcinogenic risk” indicates that at

the present time a correlation between carcinogenicity

in animals and possible human risk cannot be made

on a scientific basis, but rather only pragmatically,

with the intent of helping regulatory agencies in making decisions related to the primary prevention of

cancer. (Emphasis in original. )

The largest single testing effort is the National

Cancer Institute’s (NCI)’s Carcinogenesis Testing

Program (now a part of the National Toxicology

Program (NTP)). Griesemer and Cueto (146) analyzed the results of NCI’s testing 190 chemicals and

placed each tested chemical into one of nine classifications (see table A-l). Ninety-eight of the 190

were judged to be carcinogenic (classifications 1

through 5); 28 were equivocal (classification 6); and

64 were noncarcinogenic (classifications 7 through

9). The NCI results had earlier been reviewed by a

panel of governmental and nongovernmental experts

and Griesemer and Cueto drew on that review in

their compilation.

A significant difference between the data analyzed

by Griesemer and Cueto (hereafter referred to as the

“NCI list”) and by IARC is that all the NCI experiments were carried out according to a standard protocol (331). The IARC evaluations consider experiments carried out under a variety of protocols including those done by NCI.

Thirty-three chemicals appearing on the IARC list

of 354 also appear in the NCI list. In table 39, such

chemicals are listed in the class to which they were

assigned by Griesemer and Cueto. For instance, the

chemical chloroform appears in the NCI class 1, and

it is also present on the IARC list. Following each

listed chemical is an S, L, or 1, The letters indicate

IARC’s classifications of sufficient, limited, or inadequate evidence for carcinogenicity. In some cases,

additional data that became available between the

compilation of the 1978 (185) and 1979 (344) IARC

lists changed a chemical from I or L to S; these

changes are reflected in the table.

Comparisons between the NCI and IARC lists are

not direct because different criteria were used, but

the following scheme may be useful.

NC]

Evidence IARC classification classification

Strongly positive Sufficient evidence (S) Classes 1, 2

Positive Limited evidence (L) Classes 3, 4, 5

Not Positive Inadequate evidence (I) Classes 6, 7, 8, 9

Agreement is good about the strongly positive

chemicals, Seven of the 12 NCI class 1 chemicals

were found to have “sufficient evidence” for carcinogenicity by IARC. Of the remaining five, some

are likely to be reevaluated by IARC. For instance,

reserpine was classified in the “inadequate evidence”

group by IARC before the results of the NCI bioassay

211
212 Technologies for Determining Cancer Risks From the Environment

Table A-1 .—National Cancer Institute (NCI Analysis of the Results of Testing 190

Chemicalsa and the International Agency for Research on Cancer (IARC) Analysis

of Chemicalsb c That Appear on the NCI List

NCI Group A: Five categories of results showing increased tumor incidence, ordered with

most convincing category being number 1. -

Very strong evidence in 2 species.

317 chemicals

Chemicals among the 31 that appear on the

IARC Iists

Chlorodecone (kepone). . . . . . . . . . . . . . . . . . . . . . . . . .

Chloroform. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,4-diaminoanisole . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,4-diaminotoluene . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dibromochloropropane (DBCP) . . . . . . . . . . . . . . . . . . .

1,2-dichloroethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1,4-dioxane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5-nitroacenaphthene . . . . . . . . . . . . . . . . . . . . . . . . . . .

Phenoxybenzamine hydrochloride . . . . . . . . . . . . . . . .

Reserpine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Selenium sulfide (IARC entry is selenium

compounds) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ortho-toluidine hydrochloride . . . . . . . . . . . . . . . . . . . .

Very strong evidence in 1 species,

sufficient evidence in 2d species.

9 chemicals

None of the 9 chemicals appears on the IARC lists.

Very strong evidence in 1 species,

no evidence in 2d species.

35 chemicals

Chemicals among the 35 that appear on the

IARC lists

4-amino-2-nitrophenol. . . . . . . . . . . . . . . . . . . . . . . . . . .

Aniline hydrochloride (IARC entry is aniline) . . . . . . . .

Azobenzene ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlordane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chlorobenzilate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cinnamyl anthranilate . . . . . . . . . . . . . . . . . . . . . . . . . .

Heptachlor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lasiocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Oestradiol mustard (IARC entry is estradiol mustard)

Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Toxaphene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4-chloro-ortho-toluidine hydrochloride (IARC entry is

parachloro-ortho-toluidine hydrochloride) . . . . . . . . . .

Sufficient evidence in 2 species.

4 chemicals

None of the 4 chemicals appears on the IARC lists.

Sufficient evidence in 1 species,

no evidence in 2d species.

19 chemicals

Chemicals among the 19 that appear on the

IARC lists

Aldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethyl tellurac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Evidence for carcinogenicity, IARC

1979C

1978b

S

d —

s I — I

s

s k

s

s <

s s — L

P I

— I —e I

—

I

I

L

—

L

I

I

s

L

L—

I

— I — I

NCI Group B: One category showing insufficient evidence to lead to a conclusion about

carcinogenic it y.
Appendix A—A Comparison of NCI’s and IARC’s Evaluation of Bioassay Results ● 213

Table A-1 .—National Cancer Institute (NCI) Analysis of the Results of Testing 190

Chemicals n and the International Agency for Research on Cancer (IARC) Analysis

of Chemicalsb c That Appear on the NCI List (Continued)

Evidence for carcinogenicity, IARC

1979c

1978b

Equivocal evidence in 1 or 2 species.

28 chemicals

Chemicals among the 28 that appear on the

IARC lists

Phenacetin (tested by itself by I ARC; tested in combination with aspirin and caffeine, APC, by NCI) . . . . . . L —

Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L —

NCI Group C: Three categories showing no evidence of carcinogenicity.

No evidence in limited experiments.

51 chemicals

Chemicals among the 51 that appear on the

IARC lists

Dieldrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Endrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethionamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lindane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methoxychlor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

No evidence in 1 species.

10 chemicals

1 chemical among the 10 appears on the IARC lists

Anthranilic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

No evidence in 2 species.

3 chemicals

None of the 3 chemicals appears on the IARC lists.

L—

—

—

—

—

aGrlesemer #md Cueto, 1979.

%omatis, et al., 1978; Tomatis, 1979.

clARC, 1979; IARC, 1980.

ds Indicates “sufficient evidence of carcinogen icity. ”

L Indicates “limited evidence of carclnogenicity.”

I indicates “Inadequate evidence of carcinogen icity.”

‘See text

of that drug were available, and ortho-toluidine hydrochloride is being reevaluated by IARC. Both NCI

and IARC found that phenoxybenzamine hydrochloride is carcinogenic. Therefore the lists may only differ significantly over two chemicals, and those differences, too, may disappear as more data become

available.

Agreement is not as good about chemicals that are

less positive. NCI’s classes 3, 4, and 5 roughly correspond to IARC’s L group, but 5 of the 11 NCI class 3

compounds common to both lists were put in the “in

adequate evidence” category by IARC. Additionally,

NCI found no evidence for carcinogenicity for any

chemical in classes 6 through 9, but IARC found

“limited evidence” for carcinogenicity for five of the

eight chemicals that it reviewed in those classes.

As was mentioned, the data considered by IARC

and NCI are not independent of each other; IARC

considers NCI results in addition to all others. The

differences in classification may result from the different criteria used by the two organizations, as well

as from IARC considering other results.

Comparison of the 1978 and 1979 IARC listings

shows that the evidence for the carcinogenicity of

some chemicals became more positive. The progression to more-significant-evidence classes may be important to the contention that repeated testing increases the chances that a chemical will be determined to be a carcinogen.

Neither the IARC nor the NCI list include reviews

of all chemicals of interest. For instance, neither saccharin nor sodium nitrite appears on either list, but
. .

214 ● Technologies for Determining Cancer Risks From the Environment

both compounds have been much discussed by regulators and potentially regulated industries.

The last sentences of the Griesemer and Cueto

(146) paper draw attention to the importance attached to positive results.

Those compounds for which evidence for carcinogenicity was not found. . . cannot necessarily be considered as noncarcinogens since the tests were conducted under a limited set of circumstances. It is possible that evidence for carcinogenicity might be found

if, for example, a different strain of animal or a different route of exposure were used.

The quote illustrates the impossibility of proving a

negative, and in a more immediate sense, it also

shows that rules are not established to allow classifying a chemical as safe. A workable approach to allow

making a decision that a chemical should be regarded

as safe rather than as a potential risk may be necessary to separate important problems from minor and

nonexistent ones. In ● fact, Griesmer and Cueto’s

group C which includes four grades of negative evidence shows that conclusions can be drawn that

chemicals were found not to be risky under conditions of the tests.
Appendix B.— “Unreasonable Risk”

To learn more about the concept of “unreasonable

risk, ” the assessment made inquiries of a group of experts and cosponsored a workshop about the subject.

The inquiry was directed to 36 individuals, selected

by the Assessment Advisory Panel and OTA Staff,

and the workshop was held in March 1980 at the

New York Academy of Sciences (NYAS).

Responses to Letter Inquiries About

Unreasonable Risk

Informed individuals were asked to comment on

unreasonable risk. Each individual received the letter

and attachments shown in figure B-1. The 22 who

responded are acknowledged in table B-1.

Responses ranged from telephone calls or notes, to

reprints of papers and speeches, to discursive letters.

No attribution of a particular opinion to a specific individual is made in the description of responses that

follows. The inquiry letter was couched in reference

to the Toxic Substances Control Act (TSCA), but it

did not specify that discussions of “unreasonable

risk” were to be restricted to a balancing approach to

controlling carcinogens. Both zero-risk and balancing approaches were mentioned in the responses, but

no response mentioned a technology-based approach

to regulation.

Zero-Risk Approaches to Unreasonable Risk

A number of respondents treated cancer, especially

workplace-related cancer, as an unreasonable risk,

regardless of the number of people affected. Proponents of a purely health-based reading of unreasonable risk contend that workers should suffer

no impairment of health as a result of workplace exposures.

These responses did not reflect a naive position

that all workplace exposures can be eliminated immediately. Instead, it represented a starting position

for regulatory efforts. A respondent said that, “currently when a carcinogen is identified, the first step is

to estimate how much of it can be tolerated. ” He

would favor instead that the first step be to set as a

goal the elimination of exposure. If that is impossible, each “essential” exposure could be considered in

turn to construct a pattern of allowed exposures

above zero. Every effort should then be made to

reduce the allowed exposure.

Another respondent likened the present workplace

situation to Thomas More’s Utopian caste system, in

which laborers may be sacrificed for the greater

societal good:

Not accepting the caste system, only necessary risks

would be taken and a standard would be promulgated

acceptable to labor, but not to management . . .

[Workers] want standards set so there will be no increased risk of getting cancer as a result of their exposure to chemicals in the working environment.

Recognizing that zero exposure levels will not be possible in all situations, limiting exposure to low levels

is seen as an intermediate goal to be accomplished by

imposing every available control measure. There is

no balancing in this approach and the respondent objected to “the entire process of weighing dollar costs

to employers against the value of a human life. ”

Another respondent advocated applying all available controls for workplace exposures to known carcinogens and specifically concludes that the time for

quantitative risk assessment has not yet arrived. He

cited the continued presence of such obvious and indisputable hazards as asbestos, benzidine dyes, and

aluminum-reduction pot-room carcinogens as examples of risks which need immediate attention. He

stated that even when control techniques are available, they are not required or applied to the fullest

extent.

Interestingly, an alternative health-based approach

to unreasonable risk involves a very different methodology and leads to different actions. Quantitative

risk assessment would be used to estimate human risk

for each identified hazardous substance. All estimates would be expressed as the risk that a person

might develop cancer during his lifetime as a result of

exposure to the substance at the level now encountered. The risks would be expressed as 1/10,

1/100, 1/1,000, etc. Some value for the risk factor,

would be designated as a critical value. Risks less

than that value would be tolerated; risks greater than

that value would be declared unreasonable and candidates for regulation. Costs of regulation would not

intrude into the decision to regulate.

Balancing Approaches to Unreasonable Risk

The majority of respondents indicated a preference

for a form of balancing some combination of risks,

costs and benefits. The spectrum within this ideological grouping however, ranges from suggesting very

subjective, case-by-case determinations, to the use of

formal quantitative calculations that could be applied to all cases. Individuals who place little faith in

quantitative risk assessment and economic analysis

of costs and benefits cluster around the “subjective

and qualitative” position. The “objective and quantitative” position is occupied by people who are more

215
216 ● Technologies for D1’tmnining Cancer Risks From the Environment

Figure B-I.

Dea r

We would like your help in attacking a particularly vexing problem as part of the ongoing Assessment of Technologies for Determining Cancer Risks from the Environment. For your information, a

one page description of the Office of Technology Assessment, a one page description of the assessment, and a list of the members of the Assessment Advisory Panel are included.

In order to move against a substance under the Toxic Substance Control Act, the Administrator of

the Environmental Protection Agency must determine that the substance poses an “unreasonable

risk.” The legislative history of TSCA states that Congress decided not to attempt a definition of the

term, and intended that its use as an operational term would allow the administrator flexibility in

dealing with toxics.

We are asking a number of individuals and organizations (list enclosed) to comment on their impressions and thoughts about unreasonable risk as a concept and an operational term. The enclosed

list of questions may be useful to you. If you Iike, you may, of course, answer each one, or you can

use them as a general guide, or ignore them.

We will acknowledge all people and organizations that respond to this request in the assessment

report to be published in November, 1980. We will not attribute your comments and ideas to you

unless you ask us to do so.

I know that you are busy, and on behalf of the Assessment Advisory Panel and OTA staff, I thank

you in advance for your time and consideration.

Sincerely yours,

Michael Gough

1. Unreasonable risk, most probably, represents estimating the projected harm from continued use

of substance and balancing that against the benefits of continued use.

a. What sorts of information would you use in making estimates of the projected harm (short-term

tests, animal studies, epidemiology, specific tests. . . ?)

b. What sorts of information would you use in making estimates of the costs of restricting use of

substance?

c. How would you balance a against b?

d. Whom would you trust to supply you with the information and make the comparison?

2. What components go into determining an unreasonable risk?

a. How would you weigh each component?

b. Must the components be quantitative?

3. Isa decision about unreasonable risk tantamount to a cost-benefit or risk-benefit decision?

4. Is there an approachable numerical level for unreasonable risk?

5. Do you think we have gained anything by introduction of the term “unreasonable risk” in decision

making?

6. Have you or has your organization ever conducted an exercise that you consider to have a determination of unreasonable risk? If so, we would appreciate your describing it (or we’ll be glad to talk

to you on the phone, or if it’s already printed somewhere, just tell use the reference.)
Appendix B. –“Unreasonable Risk” . 217

Table B-1.

The OTA thanks the following individuals who responded

to a letter inquiry about unreasonable risk.

John T. Barr, Air Products and

Chemicals, Inc.

Jan Beyea, Audubon Society

Eula Bingham, Occupational Safety and

Health Administration

Ralph Engel, Chemical Specialties

Manufacturers Association

P. J. Gehring, Dow Chemical Co.

Harold P. Green, Fried, Frank, Harris,

Shriver, and Kampelman

Fred Hoerger, Dow Chemical Co,

Peter Hutt, Covington and Burling

Kenneth L. Johnson, Clement Associates, Inc.

Lorin E. Kerr, United Mine Workers of

America

Arnold Kuzmack, Environmental Protection

Agency

Linda B. Kiser, Consumer Products Safety

Commission

Lester Lave, The Brookings Institution

William J. McCarville, Monsanto Co.

Richard A. Merrill, University of Virginia

Franklin E. Mirer, United Auto Workers

F. W. Mooney, The Proctor & Gamble Co.

Parry M. Norling, E. 1. du Pent de Nemours

& Co., Inc.

Glenn Paulson, Audubon Society

David P. Rail, National Institute of

Environmental Health

Sciences

Sheldon W. Samuels American Federation of

Labor/Congress of

Industrial Organizations

confident of the precision of quantitative risk assessment and economic analysis.

A representative of the Consumer Product Safety

Commission (CPSC) described CPSC interpretation

of unreasonable risk:

The legislative history of the Consumer Product

Safety Act (CPSA) indicates that unreasonable risk of

injury is to be determined by balancing the probability that the risk will result in harm and the gravity

of the harm against a rule’s effect on the product’s

utility, cost, and availability to the consumer. Thus,

in addition to an assessment of the risk that a rule will

eliminate or reduce, an important component of unreasonable risk of injury is the economic impact of a

planned regulatory initiative. The legislative history

explains that an unreasonable risk is one which can be

prevented or reduced with little or no economic impact; or one where the rule’s effect on a product’s utility, cost or availability is outweighed by the need to

protect consumers from the hazard associated with

the product.

One respondent made the point that our knowledge of carcinogenicity forces a balancing approach.

As a policy matter, there is no recognition of a

“threshold dose:” the safe haven of a “no effect” level

does not exist for carcinogens.

The subjective qualitative approach is exemplified

by a lawyer who wrote: “A substance constitutes an

‘unreasonable risk’ only where the probability

and/or the severity of harm are deemed to outweigh

its utility.” He explained that all pertinent elements,

“probability, severity, harm, utility, ” in that statement are highly subjective, and that their definitions

are shaped by participating individuals, who may include: “legislators, regulators, business persons,

voters, writers of letters to the editor, interested

citizens, etc. ” This type of balancing emphasizes subjective judgments in qualitative determinations and

limits to purely objective determinations.

Another lawyer describes the process of unreasonable risk determinations as:

. . . paramount to a cost-benefit or risk-benefit decision. In essence, it relies as much on procedure as on

substance for correct decisions. The concept is that, if

all potentially relevant information is taken into account and all interested parties have an opportunity to

contribute to the proceedings, the ultimate decision

will be rational and as sound as it possibly can be in

an area where there is no certainty. While that is

perhaps not acceptable to a mathematician, 1 see little

possibility of improving upon it as long as the concept

remains in statutory language.

Another respondent sees the language of TSCA as

allowing a broad range of options for regulatory approaches. He suggests that TSCA rulings might follow the pattern of the Food and Drug Administration’s development of criteria for drug effectiveness

tests, beginning as loose, intuitive, ad hoc decisions,

later becoming codified into lengthy regulations.

Once that state is reached, it is difficult to depart

from the formula.

A variation on this theme came from an industrial

executive, who feels that determinations should be

qualitative, and decided on a case-by-case basis.

However, he calls for explicit criteria to be addressed

in balancing, listing as examples:

●

●

●

●

●

●

●

level of hazard inherent in exposure to the chemical;

types of exposure which create the hazard;

populations likely to be exposed;

extent of the exposed populations;

whether the exposure would be voluntary or involuntary;

availability of substitutes;

the worth to society of continued availability of

the substance;

cost inherent in various levels of control or

elimination;
218 ● Technologies for Determining Cancer Risks From the Environment

nature of the data suggesting the existence of a

hazard;

ability to extrapolate from those data to predict

the hazard in other situations; and

relative importance of regulating the particular

chemical in view of the risks presented by other

as yet unregulated chemicals.

A chemical trade association representative addressed the issue broadly:

Many criteria or approaches for one substance will

not be appropriate for another. We believe that there

is no formula for such an assessment, but that each

case must be decided on its own merits. This is not to

say that scientific methodology should not be used,

but it does say that the foundation and assumptions

that lead to the determination of “unreasonable risk”

should be clearly identified, along with their limitations, by the regulatory agency on a case-by-case

basis and not through a generic approach.

A public interest advocate deplored the high degree of quantification of risks, costs, and benefits

emanating from the Environmental Protection Agency (EPA), which are seen as based on methods inadequate to the task. The large areas of uncertainty surrounding these estimates are rarely specified, especially for economic evaluations. Risk estimates, he

feels, are good only for the grossest distinctions between the most and least potent carcinogens. Balancing, therefore, should rely heavily on qualitative

decisions, in which doubts must be resolved, by the

language of the law, in favor of greater protection.

A middle ground position is taken by many respondents, who would like to see all of the available

quantitative information enter into the final regulatory decision, but modified by such factors that

are less readily and more controversially quantified.

Within this group, there are those who feel that eventually all factors will be quantified, and that more

energy should be directed at methodologies for

reaching that goal. Others feel that certain measures,

especially the value of a human life, cannot be converted to monetary terms.

Some industry respondents lean toward quantitative approaches to deciding unreasonable risk. One

expressed his belief that risks from hazardous chemicals are overstated, and that regulation probably

will not materially benefit health. This respondent

places confidence in risk assessment:

The question of “risk” can be assessed with some

certainty. “Unreasonable” is by definition a matter of

perception, and would include consideration of the

benefits of a substance and the cost to regulate it.

As a part of risk analysis, respondents from across

the spectrum advocate risk comparisons of different

types. An industry representative thinks it would be

useful to compare the risk from exposure to a carcinogenic chemical to other risks we accept willingly in

daily life.

A highly quantitative cost-effectiveness approach

is promoted by one economist. Measures that

achieve the greatest risk reduction, most economically, would be the first to be required. This method requires risk assessments for known carcinogens and

identification of carcinogens with exposures that can

be reduced. This respondent suggested a 2-stage approach, accepting reductions to an intermediate level

which maximize risk reduction for each dollar spent,

However, final limits would be set requiring an explicit valuation of life. He acknowledges that an implicit value for life is found abhorrent by some, but,

he says: “it is inherent in all toxic substance regulation. ” This suggested scheme would not allow for a

regulation that was less cost effective than an alternative, nor any final regulation which cost more per

human life saved than the value placed on a life.

Acceptable Risk and Consumer Choice

Unreasonable risk determinations were not always

discussed in the context of a deliberative body

making a decision. Individuals, it is pointed out,

make risk-benefit decisions continuously, and much

might be learned from those behaviors in which individuals decide what risks are acceptable. Some respondents prefer to approach unreasonable risk from

a perspective of “acceptable risk. ”

An industry representative expressed the view :

. , . this more positive direction of attack is useful in

considering prospectively the extent to which regulation should be carried, as opposed to a retrospective

review to see if regulatory actions were adequate.

Amplifying, he explains:

In the long run, acceptable risk is the perceived risk

to which informed persons do not object. That statement implies a higher level of knowledge than the

general population now has, and acknowledges the

emotional issues present in any cancer controversy.

This respondent joins those who call for improvements in present methods of risk and benefit estimation, but adds:

It seems probable that them is no general answer to

acceptable risk, and no numerical value that is correct

for all situations.

The issue of whether a risk is taken voluntarily or

involuntarily is a major determinant of levels of hazard that are considered acceptable. It is supposed, in

general, that higher risk is acceptable for a purely

voluntary exposure than for an involuntary one, and

different approaches to regulation may be appropriate for different degrees of voluntarism.
Appendix B.–“Utlreas(~?lab/c Risk” ● 219

A member of the legal community, concerned particularly with consumer products, advocates a “consumer choice” approach:

. , . under which the Government would assess the

risks but would not have authority to ban on the basis

of this risk assessment, would be responsible for

assuring that information about risk is provided to

consumers through product labeling and other educational techniques, and would leave the ultimate riskbenefit judgment to consumers. The uniqueness of this

approach is that the consumer, rather than the government, would make the “regulatory” decision of

whether human exposure would occur. Some consumers would conclude that their benefits outweigh

the risks and would use the product; others would

conclude the opposite and would not use it.

Concerning the benefits derived from consumer

goods, he explains:

Most benefits are psychological or in any event

nonobjective and nonquantifiable in nature. In the

area of food . . . virtually all people eat not for health

or nutrition reasons but rather for pleasure. If one eats

enough of virtually anything that one likes, one will,

after all receive sufficient nutrition. Thus, choice of

food—i.e., consumer benefit—is wholly subjective

and personal in nature. With the exception of a very

few essential nutrients, in our country no food can be

said to have any “benefits” in the sense that they are in

any way essential or irreplaceable. And if you define

“benefits” to include simple consumer desire for

pleasure, the term soon becomes meaningless.

1 believe this same analysis holds true not just in the

area of food, but indeed for all consumer products.

And because TSCA deals with chemicals broadly, it

ultimately impacts upon all consumer goods.

Opinions Expressed in the Responses Parallel

the Diversity of Laws

From banning of carcinogens based only on consideration of risk, to balancing risks, costs, and

benefits, to an antiregulatory position of letting the

consumer decide, the responses parallel developments and discussions in regulatory law. This range

of attitudes is not surprising because many respondents have testified before the legislature or been

party to lawsuits about carcinogen regulation. On

the other hand, the spectrum of opinion confounds

conclusions that environmental laws can be fit into

an evolutionary pattern and that some approaches,

for instance, zero-risk laws, no longer have

adherents.

The evolutionary analysis suggests that more sophisticated laws, such as TSCA, with its balancing,

have now displaced risk-only approaches. Overall,

responses received by OTA indicate that risk-only

regulations are favored by some for the workplace

and that “evolution” has not displaced all interest in

risk-based regulations. In fact, the responses show

that the breadth of carcinogen regulatory approaches, including the old and the new laws, reflects

the spectrum of current thinking. The responses did

not produce a “new” approach to determining unreasonable risk. Quantitative risk assessment is an integral part of many of the responses, and its frequent

mention reflects the perceived importance of this

technique.

The New York Academy

of Sciences Meeting

The title of the NYAS meeting, “Workshop on

Management of Assessed Risk for Carcinogens, ” was

chosen to show that the focus of the meeting was not

risk assessment. The meeting lasted 2-1/2 days. There

was some overlap between participants in the meeting and respondents to the OTA letter, and because

of that and the inherent problems of capturing a long

meeting in a few pages, no attempt will be made here

to summarize the meeting. This short description will

highlight some points made there that did not arise in

any other context in this assessment.

William Ruckelshaus of the Weyerhaeuser Co., a

former EPA Administrator, was asked why industry

does not remove risks in advance of regulation. His

answer had two parts. First, he said, “industry

leaders often do not know the extent of the health or

environmental problems. ” Second, a “company that

spends money on a problem in advance of regulation

may fall behind its competitors who make the same

product but do not spend for risk reduction. ” He suggested that regulations are sometimes welcomed because all competitors are affected.

Peter Preuss described CPSC’s approach to regulation of carcinogens. Each of CPSC’s actions has

originated from a petition asking for agency action.

All but one of the chemicals had been regulated by

another agency. His analysis of CPSC actions led

him to conclude that CPSC has employed no overarching method to settle unreasonable risk questions;

each decision was largely independent of the others.

A number of speakers made the point that many

chemicals are carcinogens when tested and that there

are perhaps hundreds of candidates for regulation.

Lively discussions broke out between those who

want to order carcinogens on the basis of their potency and those who hold that extrapolation is too

imprecise to estimate potency.

Surprisingly enough, there was general agreement

about the value of cost effectiveness as a method to

plot regulatory strategy. Cost effectiveness involves

ordering the risks, estimating the cost of reducing or

eliminating the risk, and deciding which expenditure

of resources will accomplish the largest reduction in
220 . Technologies for Determining Cancer Risks From the Environment

risk. A perhaps essential difference between cost

effectiveness which found favor, and benefit-cost

analysis which did not, is that cost effectiveness

presupposes that risk reduction is a goal, and the

method guides efforts toward that goal.

There were few advocates of benefit-cost analysis

at the workshop, and many participants attacked the

method. It was characterized as expensive and as ignoring values, costs, and benefits that cannot be converted to dollars. And, for those interested in regulation, benefit-cost analysis does not set a goal of reducing risks. Instead, it puts each projected regulation to a test of whether or not it should be promulgated.

Proceedings of the workshop have recently been

published. Management of Assessed Risks for Carcinogens (276a) is a valuable source of information

about approaches to risk management.
Appendix C.—Abbreviations and Glossary of Terms

Abbreviations

2-AAF

ACS

AIHC

B(a)P

BAT

BPT

CAA

CAG

CAI

CDC

CEQ

CIIT

CPSA

CPSC

CSIN

CWA

DES

DHEW

DHHS

EPA

FDA

FDCA

FIFRA

FILS

FSC

g

GAO

GRAS

HANES

HCFA

HDL

HIS

IARC

ICD

IOM

IRLG

ITC

kg

LASS

m

mg

2-acetylaminofluorene

American Cancer Society

American Industrial Health Council

benzo(a)pyrene

best available technology

best practical technology

Clean Air Act

Carcinogen Assessment Group (EPA)

Carcinogenicity Activity Indicator

Centers for Disease Control (PHS)

Council on Environmental Quality

Chemical Industry Institute of Toxicology

Consumer Product Safety Act

Consumer Product Safety Commission

Chemical Substances Information Network

(EPA)

Clean Water Act

diethylstilbestrol

Department of Health, Education, and

Welfare

Department of Health and Human Services

Environmental Protection Agency

Food and Drug Administration (PHS)

Food, Drug, and Cosmetic Act

Federal Insecticide, Fungicide, and

Rodenticide Act

Federal Information Locator System

Food Safety Council

gram

General Accounting Office

generally recognized as safe

Health and Nutrition Examination Survey

(NCHS)

Health Care Financing Administration

(DHHS)

high dose level

Health Interview Survey (NCHS)

International Agency for Research on

Cancer (WHO)

International Classification of Diseases

(WHO)

Institute of Medicine (NAS)

Interagency Regulatory Liaison Group

Interagency Testing Committee

kilogram (1,000 g)

Linked Administrative Statistical Sample

meter

milligram (one-thousandth of a gram;

10-3 g)

MTD

NAS

NCAB

NCHS

NCI

NCTR

NDI

ng

NIEHS

NIH

NIOSH

NOHS

NORS

NRC

NRDC

NSF

NTP

OECD

OHRST

maximum tolerated dose

National Academy of Sciences

National Cancer Advisory Board

National Center for Health Statistics

(DHHS)

National Cancer Institute (NIH)

National Center for Toxicological Research

(EPA/FDA)

National Death Index (NCHS)

nanogram (one-billionth of a gram; 10-9 g)

National Institute of Environmental Health

Sciences

National Institutes of Health (PHS)

National Institute of Occupational Safety

and Health (CDC)

National Occupational Hazard Survey

(NIOSH)

National Organics Reconnaissance Survey

(EPA)

National Research Council (NAS)

Natural Resources Defense Council

National Science Foundation

National Toxicology Program (DHHS)

Organization for Economic Cooperation

and Development

Office of Health Research, Statistics, and

Technology

OSH Act Occupational Safety and Health Act

OSHA

OSTP

PAH

PCBs

PHS

PMN

RCRA

RPAR

SAB

SDWA

SEER

SNUR

SSA

TSCA

TSSC

ug

WHO

Occupational Safety and Health

Administration (Department of Labor)

Office of Science and Technology Policy

polycyclic aromatic hydrocarbons

polychlorinated biphenyls

Public Health Service (DHHS)

premanufacturing notice

Resource Conservation and Recovery Act

rebuttable presumption against registration

Scientific Advisory Board (EPA)

Safe Drinking Water Act

Surveillance, Epidemiology, and End

Results program (NCI)

significant new use rule

Social Security Administration (DHHS)

Toxic Substances Control Act

Toxic Substances Strategy Committee

microgram (one-millionth of a gram;

10-’ g)

World Health Organization (United

Nations)

221
222 ● Technologies for Determining Cancer Risks From the Environment

Glossary of Terms

Benign tumor: A tumor confined to the territory in

which it arises, not invading surrounding tissue

or metastasizing to distant organs. Benign tumors

can usually be excised by local surgery.

Carcinoma: Cancers of the epithelia, including the

external epithelia (mainly skin and linings of the

gastrointestinal tract, lungs, and cervix) and the

internal epithelia that line various glands (e.g.,

breast, pancreas, thyroid).

Bioassay: In general, a test in living organisms. As

used in this report, a test for carcinogenicity in

laboratory animals, generally rats and mice,

which includes near-lifelong exposure to the agent

under test. Used interchangeably with “animal

test .“

Carcinogen: A substance that causes cancer.

Epigenetic: As used in reference to cancer, an effect

on cancer causation that does not directly involve

an interaction with DNA.

Epitheliums: The covering of internal and external

surfaces of the body, including the lining of vessels and other small cavities.

Incidence: The number of new cases of a disease,

usually expressed as a rate:

Number of new cases of a disease occurring in a population

during a specified period of time

Number of persons exposed to risk of developing the disease

during that period of time

The incidence rate is a direct estimate of the probability, or risk, of developing a disease during a

specified period of time.

Initiator: An external stimulus or agent that produces

a cell that is “latently premalignant. ” An initiation event, or more generally, an early event,

may be a mutational change in the cell’s genetic

material, but the change is unexpressed, and it

causes no detectable change in the cell’s growth

pattern. The change is considered to be irreversible.

Leukemia: Cancers of the blood-forming organs,

characterized by abnormal proliferation and development of leukocytes (white blood cells) and

their precursors in the blood and bone marrow.

Lymphoma: Cancers of cells of the immune system,

i.e., the various types of lymphocytes. Hodgkin’s

disease is included among the lymphomas.

Malignant tumor: A tumor that has invaded neighboring tissue and/or undergone metastasis to distant body sites, at which point the tumor is called

a cancer and is beyond the reach of local surgery.

Melanoma: A tumor made up of melanin-pigmented

cells. As used in this report, “malignant melanoma, ”

Mesothelioma: A tumor developing from a cell on

the surface of the peritoneum (the membrane lining the abdominal cavity), pericardium (the membrane enclosing the heart), or pleura (the membrane lining each half of the thorax).

Metastasis: The spread of a malignancy to distant

body sites by cancer cells transported in blood or

lymph circulation.

Morbidity: The condition of being diseased.

Mortality rate: The death rate, often made explicit

for a particular characteristic, e.g., age, sex, or

specific cause of death. A mortality rate contains

three essential elements: 1) the number of people

in a population group exposed to the risk of

death; 2) a time factor; 3) the number of deaths

occurring in the exposed population during a certain time period. For example, the annual U.S.

cancer mortality rate is:

Number of deaths from cancer in the United States during 1 year

Number of people in the population at midyear

Mutagen: A chemical or physical agent that interacts

with DNA to cause a permanent, transmissible

change in the genetic material of a cell.

Myelomatosis: A malignant neoplasm of plasma cells

usually arising in the bone marrow. Also called

multiple myeloma.

Neoplasm: A new growth of tissue in which growth

is uncontrolled and progressive. A tumor.

Nonmelanoma: Skin cancer of two types: basal cell

and squamous cell carcinomas. Though these tumors may invade surrounding tissue, and therefore are technically cancers, they seldom metastasize and are usually successfully treated with

local surgery. Because they are relatively easily

treated, often outside hospitals, cause relatively

few deaths, and are not often enumerated, they

are usually excluded from cancer statistics.

Prevalence: The number of existing cases of a disease, usually expressed as a rate:

Number of cases of a disease present in the population at

(or during) a specified time (period)

Number of persons in the populaton at

(or during) the specified time

Promoter: An influence or agent causing an initiated

cell to produce a tumor. Promotion events, or

more generally, late events, can occur only in
Appendix C. —Abbreviations and Glossary ● 223

“initiated” cells, and are somewhat reversible.

Discontinuation of exposure to a promoter, if exposure has not yet caused a tumor, may prevent

the appearance of a tumor.

Sarcoma: Cancers of various supporting tissues of

the body (e. g., bone cells, blood vessels, fibrous

tissue cells, muscle).

Short-term test: Tests that take less time to complete

than do bioassays. Most of these tests biologically

measure interactions between the agent under test

and DNA. Agents that have effects in short-term

tests are considered more likely to be carcinogens

than those that have no effect.

Transformed cell: A cell that has undergone both initiation and promotion, and will eventually give

rise to a tumor.

Tumor: A new growth of tissue in which growth is

uncontrolled and progressive. A neoplasm.

1.

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