Chemical Risk Assessment: Selected Federal Agencies' Procedures, Assumptions, and Policies
Published: 2001-08-06T00:00:00

Fast Facts:

Highlights:
section_title: What GAO Found
paragraphs: As used in public health and environmental regulations, risk assessment is the systematic, scientific description of potential harmful effects of exposures to hazardous substances or situations. It is a complex but valuable set of tools for federal regulatory agencies to identify issues of potential concern, select regulatory options, and estimate the range of a forthcoming regulation's benefits. However, given the significant yet controversial nature of risk assessments, it is important that policymakers understand how they are conducted, the extent to which risk estimates produced by different agencies and programs are comparable, and the reasons for differences in agencies' risk assessment approaches and results. GAO studied the human health and safety risk assessment procedures of the Environmental Protection Agency, the Food and Drug Administration, the Occupational Safety and Health Administration, and the Department of Transportation's Research and Special Programs Administration. This report describes (1) the agencies' chemical risk assessment activities, (2) the agencies primary procedures for conducting risk assessments, (3) major assumptions or methodological choices in their risk assessment procedures, and (4) the agencies' procedures or policies for characterizing the results of risk assessments.

section_title: Letter
paragraphs: national ambient air quality standards National Academy of Sciences National Center for Toxicological Research no observed adverse effect level no observed effect level National Research Council Office of Air Quality Planning and Standards Office of Air and Radiation Office of Emergency and Remedial Response Office of Hazardous Materials Safety Office of Hazardous Materials Technology Office of Pesticide Programs Office of Pollution Prevention and Toxics Office of Prevention, Pesticides and Toxic Substances Office of Research and Development Occupational Safety and Health Administration Office of Solid Waste Office of Water physiologically based pharmacokinetic permissible exposure limit premanufacture notification point of departure Resource Conservation and Recovery Act reference concentration reference dose relative source contribution Research and Special Programs Administration structure-activity relationship Superfund Amendments and Reauthorization Act Safe Drinking Water Act standard operating procedures short-term exposure limit tolerable intake Toxic Substances Control Act time-weighted average upper confidence limit United Nations United States Coast Guard United States Department of Agriculture As used in public health and environmental regulation, risk assessment is  the systematic, scientific description of potential adverse effects of  exposures to hazardous substances or situations.  It is a complex but  valuable set of tools for federal regulatory agencies, helping them to  identify issues of potential concern, select regulatory options, and estimate  the range of a forthcoming regulation’s benefits.  For example, the  Environmental Protection Agency (EPA) used risk assessment information  in a 1998 final rule to conclude that disinfection byproducts (e.g.,  chloroform) in drinking water could cause as many as 9,300 bladder cancer  cases a year, and that a 24-percent reduction in those byproducts could  result in monetized health benefits of about $4 billion.  However, risk  assessments are also sometimes controversial, as evidenced by the fact  that the disinfection byproduct rule was successfully challenged in court  over whether the agency used the best scientific evidence available in  support of certain assumptions.  Given the significant yet controversial  nature of risk assessments, it is important that policymakers understand  how risk assessments are conducted, the extent to which risk estimates  produced by different agencies and programs are comparable, and the  reasons for differences in agencies’ risk assessment approaches and  results.
You asked us to provide information on selected federal agencies’ risk  assessment procedures and the similarities and differences in how the  agencies’ personnel are directed to conduct risk assessments.  As you  requested, our review focused on the human health and safety (and, to a  lesser extent, ecological) risk assessment procedures of the following four  agencies with primary responsibility for regulating or managing risks from  potential exposure to chemicals: (1) EPA; (2) the Food and Drug  Administration (FDA) within the Department of Health and Human  Services (HHS); (3) the Occupational Safety and Health Administration  (OSHA) within the Department of Labor; and (4) the Department of  Transportation’s (DOT) Research and Special Programs Administration  (RSPA).  These agencies regularly conduct chemical risk assessments in  support of regulatory activities and/or illustrate the diversity of risk  assessment procedures.  Our primary objectives were to identify and  describe (1) the general context for the agencies’ chemical risk assessment  activities; (2) what the agencies view as their primary procedures for  conducting risk assessments; (3) what the agencies view as their major  assumptions or methodological choices in their risk assessment  procedures; and (4) the agencies’ procedures or policies for characterizing  the results of risk assessments.  In addressing each of these objectives, we  also identified similarities and differences between and within the  agencies.  To the extent feasible, we were also asked to identify as part of  the third objective, (a) at what stages of the risk assessment process the  assumptions are used, (b) the reasons given for their selection, (c) their  likely effects on risk assessment results, and (d) how they compare to the  assumptions and choices used by other agencies or programs in similar  circumstances.
We addressed these objectives by reviewing agencies’ general guidance  documents or, if there were no such documents, specific examples of  agencies’ risk assessment procedures.  We also reviewed previous reports  on agencies’ procedures, interviewed agency officials, and provided  detailed descriptions of the relevant procedures to agency officials for their  review and comment.  Our review focused on chemical risk assessments in  selected agencies, and therefore did not cover all types of risk assessments  or even all agencies or programs that conduct chemical risk assessments.   Also, our review did not evaluate how the selected agencies’ procedures  and policies are applied in individual risk assessments, or how risk  assessment results are used in making regulatory decisions (risk  management).  We provided a draft of this report to five risk assessment  experts to ensure technical accuracy.  We also provided a draft to officials  in each of the four agencies for their review and comment.  The comments  that we received from both the experts and the agencies are reflected in the  “Agency Comments and Our Evaluation” section of this letter.  We  conducted this review between February 2000 and March 2001 in  accordance with generally accepted government auditing standards.   Details of our scope and methodology are presented in appendix I.
subsections: section_title: Background
paragraphs: Risk assessments are conducted to estimate whether and/or how much  damage or injury can be expected from exposures to a given risk agent and  to assist in determining whether these effects are significant enough to  require action, such as regulation.  The effects of concern can be diseases  such as cancer, reproductive and genetic abnormalities, workplace injuries,  or various types of ecosystem damage.  The risk agent analyzed in an  assessment can be any number of things, including chemicals, radiation,  transportation systems, or a manufacturing process.  The product of a risk  assessment is a quantitative and/or qualitative statement regarding the  probability that an exposed population will be harmed and to what degree.
Risk assessment, particularly quantitative risk assessment, is a relatively  new discipline, developed in the first half of the 20th century to establish  various health and safety codes and standards.  The role of risk assessment  in the regulatory process was accelerated by the enactment of various  health, safety, and environmental statutes in the early 1970s.  The  development of chemical risk assessment procedures has traditionally  followed two different tracks—one for assessments of cancer risks and  another for assessments of noncancer risks.  The procedures associated  with cancer risks have historically assumed that there is no “threshold”  below which an agent would not cause adverse effects.  In contrast,  procedures for assessments of noncancer risks were largely developed  under the assumption that there is such a threshold—that exposures up to  a certain level would not be expected to cause harm.
In 1983, NAS identified four steps in the risk assessment process:   (1) hazard identification (determining whether a substance or situation  could cause adverse effects), (2) dose-response assessment (determining  the relationship between the magnitude of exposure to a hazard and the  probability and severity of adverse effects), (3) exposure assessment  (identifying the extent to which exposure actually occurs), and (4) risk  characterization (combining the information from the preceding analyses  into a conclusion about the nature and magnitude of risk).  This paradigm,  originally intended to address assessments of long-term health risks, such  as cancer, has become a standard model for conducting risk assessments,  but is not the only model (e.g., different models are used for ecological risk  assessments).  According to NAS, the results of the risk assessment  process should be conceptually distinguished from how those results are  used in the risk management process (e.g., the decision on where to  establish a particular standard).  As illustrated by figure 1, the risk  management decision considers other information in addition to the risk  characterization.
More recent reports have updated and expanded on these original  concepts.  In 1996, NAS urged risk assessors to update the original concept  of risk characterization as a summary added at the end of a risk  assessment.  Instead, the report suggested that risk characterization  should be a “decision-driven” activity directed toward informing choices  and solving problems and one that involves decision makers and other  stakeholders from the very inception of a risk assessment.  In this updated  view, the nature and goals of risk characterization are dictated by the goals  of the risk management decisions to be made.  Similarly, the  Presidential/Congressional Commission on Risk Assessment and Risk  Management (hereinafter referred to as the Presidential/Congressional  Commission) recommended in 1997 that the performance of risk  assessments be guided by an understanding of the issues that will be  important to risk management decisions and to the public’s understanding  of what is needed to protect public health and the environment.
subsections: section_title: Data on Chemical Health Effects and Exposures Are Limited
paragraphs: Substantial numbers and amounts of chemical substances and mixtures are  produced, imported, and used in the United States.  For example, there are  over 70,000 commercial chemicals in EPA’s Toxic Substances Control Act  (TSCA) Chemical Substances Inventory, and the agency receives about  1,500 petitions each year requesting the approval of new chemicals or new  uses of existing chemicals.  However, there is relatively little empirical  data available on the toxicity of most chemicals and the extent to which  people or the environment might be exposed to the chemicals.  For  example, we previously reported that EPA’s Integrated Risk Information  System (IRIS), which is a database of the agency’s consensus on the  potential health effects of chronic exposure to various substances found in  the environment, lacks basic data on the toxicity of about two-thirds of  known hazardous air pollutants.  Furthermore, to the extent that data on  health effects are available, the data are more often from toxicological  studies involving animal exposures than from epidemiological studies  involving human exposures.  As a consequence, chemical risk assessments  must rely often on extrapolation from animal studies and are quite different  from risk assessments that use epidemiological studies or actuarial data  (such as accident statistics).
The limited nature of information on chemical toxicity was illustrated in a  1998 EPA report on the data that were publicly available on approximately  3,000 high-production-volume (HPV) chemicals.  For each of these  chemicals, EPA examined the available data corresponding to six basic  tests that have been internationally agreed to as necessary for a minimum  understanding of a chemical’s toxicity.  As shown in figure 2, the agency  concluded that the full set of basic toxicity data was available for only  about 200 (7 percent) of the chemicals, and that 43 percent of the  chemicals did not have publicly available data for any of the six tests.
There are also significant gaps in the available data on the extent to which  people are exposed to chemicals.  For example, last year we reviewed  federal and state efforts to collect human exposure data on more than 1,400  naturally occurring and manmade chemicals considered by HHS, EPA, and  other entities to pose a threat to human health. We reported that, taken  together, HHS and EPA surveys measured the degree of exposure in the  general population for only 6 percent of those chemicals.  Even for those  chemicals that were measured, information was often insufficient to  identify smaller population groups at high risk (e.g., women, children, and  the elderly).
section_title: Uncertainty Contributes to Controversy about Chemical Risk Assessment
paragraphs: There is an ongoing debate about the appropriate application of risk  assessment in federal regulation.  In 1990, Congress mandated that a  commission be formed to “make a full investigation of the policy  implications and appropriate uses of risk assessment and risk management  in regulatory programs under various Federal laws to prevent cancer and  other chronic human health effects which may result from exposure to  hazardous substances.”  The Presidential/Congressional Commission  published its final report in 1997, and noted that often “the controversy  arises from what we don’t know and from what risk assessments can’t tell  us.”  NAS has also emphasized that science cannot always provide  definitive answers to questions raised during the course of conducting a  risk assessment, so risk assessors must use assumptions throughout the  process that reflect professional judgments and policy choices.
One focus of the risk assessment debate has been agencies’ use of  precautionary assumptions and analytical methods.  The term  “precautionary” refers to the use of methods and assumptions that are  intended to produce estimates that should not underestimate actual risks.   Some critics of federal risk assessment practices believe agencies use  assumptions that are unjustifiably precautionary in the face of new  scientific data and methods, thereby producing estimates that overstate  actual risks.  The critics contend that this effect is compounded when  multiple precautionary assumptions are used.  Others, however, criticize  agency practices for not being precautionary enough in the face of  scientific uncertainties, failing, for example, to adequately account for the  synergism of exposures to multiple chemicals or the risks to persons most  exposed or most sensitive to a particular toxic agent.  Other observers,  including NAS, have expressed concerns about whether the agencies’  procedures and assumptions are sufficiently transparent, thereby providing  decision makers and the public with adequate information about the  scientific and policy bases for agencies’ risk estimates as well as the  limitations and uncertainties associated with those estimates.
We have discussed these issues in several previous reports. For example, in  1993, we noted that EPA used precautionary assumptions throughout the  process that it used to assess risk at Superfund hazardous waste sites, and  that the agency had been criticized for overstating risk by combining  precautionary estimates.  In September 2000, we reported on EPA’s use of  precautionary “safety factors” pursuant to the Food Quality Protection Act  of 1996.  In October 2000, we said that three factors influenced EPA’s use  of precautionary assumptions in assessing health risks: (1) the agency’s  mission to protect human health and safeguard the natural environment,  (2) the nature and extent of relevant data (e.g., animal versus human  studies), and (3) the nature of the health risk being evaluated (e.g., cancer  versus noncancer risks).
section_title: Context for Agencies’ Chemical Risk Assessments Is Important
paragraphs: The context in which chemical risk assessments are conducted plays an  important role in determining what type of assessments federal regulatory  agencies perform and why certain approaches are used.  Two dimensions  seem particularly important to understanding the context for an agency’s  chemical risk assessment activities: (1) the general statutory and legal  framework underlying the agency’s regulation of chemicals and (2) how the  agency plans to use the risk assessment information.  The statutory and  legal framework determines the general focus and goals of an agency’s  chemical risk assessment activities and also can shape how risk  assessments for those activities are supposed to be conducted.  The  specific tasks and purposes for which an agency will use the results of a  particular risk assessment determine the questions that the assessment  needs to address and the scope and level of detail of the assessment.
subsections: section_title: Statutory and Legal Framework
paragraphs: A diverse set of statutes addresses potential health, safety, and  environmental risks associated with chemical agents.  These statutory  mandates generally focus on different types and sources of exposure to  chemicals, such as consumption of pesticide residues in foods,  occupational exposures to chemicals, or inhalation of toxic air pollutants.   Therefore, different agencies (and different offices within those agencies)  have distinctive concerns regarding chemical risks.  For example, each  major program office within EPA (e.g., the Office of Air and Radiation or  the Office of Water) is responsible for addressing the risk-related mandates  of one or more statutes (e.g., the Clean Air Act, the Clean Water Act, or the  Safe Drinking Water Act).  Also, international agreements provide  important legal context for transportation risk assessment activities.  For  example, criteria for classifying dangerous chemicals in transportation  have been internationally harmonized through the United Nations’  Recommendations on the Transport of Dangerous Goods.
The legal framework underlying chemical regulation influences both the  extent to which risk assessment is needed for regulatory decision making  and how risk assessments are supposed to be conducted.  Some statutes  require regulatory decisions to be based solely on risk (considering only  health and environmental effects), some require technology-based  standards (such as requiring use of the best available control technology),  and still others require risk balancing (requiring consideration of risks,  costs, and benefits).  For example, section 112 of the Clean Air Act (CAA),  as amended, has a technology-based mandate requiring the use of the  maximum achievable control technology to control emissions of hazardous  air pollutants.  A risk assessment is not needed to determine such  technology, but would be used to evaluate residual risks that remain after  that technology is in use.  Some statutes also place the primary  responsibility for conducting risk assessments and compiling risk-related  data for a particular chemical or source of exposure to chemical agents  with industry, states, or local entities, rather than with the federal  regulatory agencies.  For example, industry petitioners have the primary  responsibility to provide the data needed to support registration and  tolerances from EPA for their pesticides, including information on the  toxicological effects of the pesticides.
Statutes can also affect risk assessment by specifically defining what will  be considered a hazard, directing the agency to take certain  methodological steps, or specifying the exposure scenario of regulatory  concern.  For example, in response to the “Delaney Clause” amendments to  the Federal Food, Drug, and Cosmetic Act, FDA identifies any food additive  for which an adequately conducted animal cancer study indicates that the  additive produces cancer in animals as a carcinogen under the conditions  of the study.  No further corroboration or weight-of-evidence analysis is  required.  The Food Quality Protection Act of 1996 requires EPA to add an  additional 10-fold safety factor to protect infants and children when  deriving standards for allowable pesticide residues in foods, unless reliable  data show that a different factor will be safe.  Provisions in the  Occupational Safety and Health Act focus OSHA’s risk assessments on  estimating the risks to workers exposed to an agent for a working lifetime.
However, in most cases the statutes simply provide a general framework  within which the agencies make specific risk assessment assumptions and  methodological choices.  For example, section 109 of the CAA requires EPA  to set national ambient air quality standards that in the judgment of the  EPA Administrator—and allowing for an “ample margin of safety”—are  requisite to protect the public health.  EPA risk assessors translate that  general requirement into specific risk assessment assumptions and  methods (e.g., whether to assume a threshold or no-threshold relationship  between dose and response at low doses).
section_title: Use of Risk Assessment Results
paragraphs: The specific purpose or task of an assessment determines the kinds of risk  information needed for the agency to make its risk management decisions,  and can significantly influence the scope and level of detail required of a  risk assessment.  For example,  If the agency’s task is to set a specific health-based standard (e.g., a  national air quality standard), a rigorous and detailed estimate of risks at  particular exposure levels might be required.
If the agency’s task is to decide whether to approve the production and  use of commercial chemicals or pesticides, risk assessors may initially  focus on potential upper-bound exposures (e.g., assuming that a  chemical agent will be used at the maximum level permitted by law or  focusing on individuals who consume the greatest amounts of a food  containing residues of the agent at issue).  If such upper-bound  estimates exhibit no cause for concern, the agency may have no need to  complete a more comprehensive and refined risk assessment.
A decision on whether to add or remove a chemical from the list of  potential hazards might focus the risk assessors on determining whether  the potential risk is above or below a specific threshold level, such as  the risk of 1 extra cancer case over the lifetime of 1 million people.
The influence of the specific regulatory task at hand is illustrated by a  method commonly used by agencies for risk assessments of noncancer  health effects.  Agencies such as EPA and FDA have historically attempted  to identify a dose level of a chemical associated with no observed adverse  effect level (NOAEL) in animal experiments—or the lowest observed  adverse effect level (LOAEL) in the study, if every tested dose exhibited  some effect.  They then divided that NOAEL or LOAEL dose by multiple  “safety” or “uncertainty” factors to account for the possibility that humans  may be more sensitive to the chemical than animals and other  uncertainties.  This procedure is designed to identify a dose not likely to  result in harm to humans, not to provide an explicit quantitative estimate of  the risks associated with a given chemical.  In other words, sometimes the  focus of federal agencies’ “risk” assessments could more accurately be  described as a safety assessment (i.e., estimating a “safe” level of exposure  to chemical agents or a dose below which no significant risk is expected to  occur) rather than a risk assessment (i.e., estimating the actual risks  associated with exposures to chemical agents).
section_title: Implications of Contextual Differences
paragraphs: Because of contextual differences, the risk assessment procedures used,  the resulting risk estimates (and regulatory actions based upon those  estimates), and even whether a substance would be subject to risk  assessment, can vary among different agencies and programs within the  same agency.  The following examples illustrate how contextual  differences affect the conduct of risk assessments.
Because regulation of certain wastes may be impractical or otherwise  undesirable, regardless of the hazards that the waste might pose,  Congress and EPA exempted certain materials (e.g., agricultural or  mining and mineral processing wastes) from the definitions of  hazardous wastes.  If a material meets one of the categories of  exemptions, it cannot be identified as a hazardous waste even if it  otherwise meets the criteria for listing as a hazardous waste.  For  example, according to EPA’s RCRA Orientation Manual, wastes  generated in raw material, product storage, or process (e.g.,  manufacturing) units are exempt from EPA’s hazardous waste regulation  while the waste remains in such units.  However, OSHA might assess  and regulate risks associated with such materials as part of its mission  to protect the health of employees in the workplace.
FDA and EPA both assess potential human health risks associated with  ingestion of chemical substances.  If a substance is being assessed by  FDA as a food additive and results from any adequate study indicate that  the substance produces cancer in animals, FDA labels that additive as a  carcinogen without considering other scientific evidence (per the  Delaney clause of the Federal Food, Drug, and Cosmetic Act, as  amended).  However, when assessing the risks associated with  consumption of residues from animal drugs (FDA) and pesticides (EPA)  the agencies may need to consider many scientific studies in  determining whether and under what conditions an agent might cause  cancer or other adverse health effects in humans.
EPA’s risk assessments of commercial chemicals under TSCA vary  depending on whether the chemical at issue is “existing” or “new.”  For  EPA to control the use of an existing chemical, the agency must make a  legal finding that the chemical will present an unreasonable risk to  human health or the environment.  EPA said this standard requires the  agency to have conclusive data on risks associated with that particular  chemical.  By comparison, newly introduced chemicals can be regulated  based on whether they may pose an unreasonable risk, and this finding  of risk can be based on data for structurally similar chemicals, not just  data on that particular chemical.  Because industrial chemicals in  commerce were “grandfathered” under TSCA into the inventory of  existing chemicals more than 20 years ago, without considering whether  they were hazardous, there are situations in which existing chemicals  might not be controlled while, at the same time, EPA would act to  control a new chemical of similar or less toxicity.
Within EPA’s Office of Water, risk assessments vary depending on  whether the assessment is done to establish drinking water standards or  standards for ambient water (e.g., bodies of water such as lakes and  rivers).  Risk assessments for drinking water standards focus solely on  human health effects, but assessments used to establish ambient water  quality criteria consider both human health and ecological effects.  Even  when considering just the human health risks, an important difference  between the ambient and drinking water risk assessments is an  additional focus for ambient water on exposures to contaminated water  through consumption of contaminated fish or shellfish.  This additional  factor is a primary reason for potential differences in drinking water and  ambient water risk estimates and standards for the same chemical.
Appendices II through V describe the relevant contextual factors for each  of the four selected agencies in greater detail.
section_title: Agencies’ Risk Assessment Procedures Share Common Features, But Substantive Differences Also Exist
paragraphs: All four of the agencies included in our review have standard procedures  for conducting risk assessments, although the agencies vary in the extent  to which their procedures are documented in written guidance.  In general,  there are more similarities than differences across EPA, FDA, and OSHA  procedures, because each of these agencies generally follows the four-step  NAS risk assessment process.  The procedures address the same basic  questions regarding hazard identification, dose-response assessment, and  exposure assessment.  The specific analytical methods and approaches in  those procedures are also very similar (e.g., extrapolating from animal  study data to model dose-response relationships in humans, and generally  using different procedures for assessing cancer and noncancer risks).  The  most substantive differences across and within these agencies are related  to exposure assessment, reflecting the diversity in the agencies’ regulatory  authorities regarding chemical agents across different kinds or sources of  exposure.  For example, both OSHA and EPA consider methylene chloride  (also known as dichloromethane) to be a probable human carcinogen.   However, this same chemical can be identified as a significant hazard by  one agency in one exposure setting (OSHA for purposes of assessing health  risks associated with occupational exposures) but as a low hazard by  another agency in a different setting (EPA for purposes of Superfund  hazard ranking screening).  RSPA, although sharing a concern over  identifying risks and analyzing their consequences and probabilities of  occurrence, has a different structure to its risk assessments than the other  three agencies because of its focus on risks associated with unintentional  releases of hazardous materials during transportation.  In general, all four  agencies are incorporating more complex analytical models and methods  into their risk assessment procedures.  However, some of the advanced  models require much more detailed information than may be currently  available for many chemicals.
subsections: section_title: Risk Assessment Procedures at EPA
paragraphs: EPA has extensive written internal risk assessment procedures.  For  example, EPA has agencywide guidelines, policy memoranda, and  handbooks covering the following aspects of risk assessment:  carcinogen risk assessment,  neurotoxicity risk assessment,  reproductive toxicity risk assessment,  developmental toxicity risk assessment,  mutagenicity risk assessment,  health risk assessment of chemical mixtures,  exposure assessment,  ecological risk assessment,  evaluating risk to children,  use of probabilistic analysis in risk assessment,  use of the benchmark dose approach in health risk assessment, and  use of reference dose and reference concentration in health risk  assessment.
EPA also has numerous program-specific guidelines and policy documents,  such as the Risk Assessment Guidance for Superfund series and a set of  more than 20 science policy papers and guidelines from the Office of  Pesticide Programs in response to the Food Quality Protection Act of 1996.   Many of the agency’s guidance documents are draft revisions to earlier  documents or procedures or draft guidance on new issues that have not  previously been addressed by EPA.  Although such drafts are not yet final,  official statements of agency policies or procedures, they may better  represent the current practice of risk assessment in EPA than earlier “final”  documents.
EPA generally follows the NAS four-step risk assessment process.  (The  major exception is the agency’s Chemical Emergency Preparedness and  Prevention Office, which follows a different set of procedures because of  its focus on risks associated with accidental chemical releases from fixed  facilities.  See app. II for a discussion of this office’s risk assessment  procedures.)  EPA’s risk assessment activities generally involve both the  program offices (e.g., the Office of Air and Radiation or the Office of Solid  Waste) and the Office of Research and Development (ORD), which is the  principal scientific and research arm of the agency.  ORD often does risk  assessment work for EPA program offices that focuses on the first two  steps in the four-step NAS process—hazard identification and dose- response assessment—in particular, the development of “risk per unit  exposed” numbers.  Preparation of the final two steps in the process— exposure assessment and risk characterization—tends to be the  responsibility of the relevant program offices.  Several programs, for  example, frequently use a single hazard assessment, but for different  exposure scenarios.  There are, however, exceptions to this generalization.   For example, ORD carries out all steps for highly complex, precedent- setting risk assessments, such as those for dioxin and mercury.  There are  also instances when EPA program offices carry out all four steps of the  process.  In some situations, EPA agencywide procedures also depart  slightly from the NAS paradigm.  For example, when assessing noncancer  health effects, EPA’s normal practice is to do hazard identification in  conjunction with the analysis of dose-response relationships, rather than as  distinct steps.  According to EPA’s guidelines, this is because the  determination of a hazard is often dependent on whether a dose-response  relationship is present.  In the case of ecological risk assessments, EPA’s  guidelines suggest a three-step process consisting of (1) problem  formulation, (2) analysis, and (3) risk characterization, rather than the four- step process used for health risk assessments.
EPA has identified several new directions in its approach to exposure  assessment.  First is an increased emphasis on total (aggregate) exposure  to a particular agent via all pathways.  EPA policy directs all regulatory  programs to consider in their risk assessments exposures to an agent from  all sources, direct and indirect, and not just from the source that is subject  to regulation by the office doing the analysis.  Another area of growing  attention is the consideration of cumulative risks, when individuals are  exposed to many chemicals at the same time.  The agency is also increasing  its use of probabilistic modeling methods to analyze variability and  uncertainty in risk assessments and provide better estimates of the range of  exposure, dose, and risk to individuals in a population than are provided by  single point estimates.  EPA’s guidance on probabilistic methods outlines  standards that exposure data prepared by industry or other external  analysts must meet to be accepted by EPA.
section_title: Risk Assessment Procedures at FDA and OSHA
paragraphs: FDA and OSHA also generally follow the NAS risk assessment paradigm,  but neither FDA nor OSHA had written internal guidance specifically on  conducting risk assessments at the time of our review.  However, both  agencies’ standard procedures are well documented in the records of  actual risk assessments and in summary descriptions that have appeared in  scientific and professional literature.  In addition, FDA has published  volumes of guidance on risk assessments for use by external parties  affected by the agency’s regulations (e.g., animal drug manufacturers  seeking FDA approval for their products).  According to FDA officials, the  documents are meant to represent the agency’s current thinking on the  scientific data and studies considered appropriate for assessing the safety  of a product, and sometimes include detailed descriptions of the risk  assessment methods deemed appropriate to satisfy FDA’s requirements  under various statutory provisions.  However, these guidelines do not  preclude the use of alternative procedures by either FDA or external  parties.
The responsibility for conducting risk assessments in FDA is divided  among the agency’s program offices.  For example, FDA’s Center for Food  Safety and Applied Nutrition (CFSAN) is responsible for assessing risks  posed by food additives and contaminants, while the Center for Veterinary  Medicine (CVM) is responsible for assessing risks posed by animal drug  residues in food.  In addition, FDA’s National Center for Toxicological  Research conducts scientific research to support the agency’s regulatory  needs, including research aimed at understanding the mechanisms of  toxicity and carcinogenicity and at developing and improving risk  assessment methods.  FDA officials said that there are variations in the risk  assessment approaches used among the agency’s different product centers  and, in some cases, within those centers.  In general, those variations are  traceable to differences in factors such as the substances being regulated,  the nature of the health risks involved (particularly carcinogens versus  noncarcinogens), and whether the risk assessment is part of the process to  review and approve a product before it can be marketed and used  (premarket) or part of the process of monitoring risks that arise after a  product is being used (postmarket).  For example, risk assessments by  CFSAN’s Office of Food Additive Safety and Office of Nutritional Products,  Labeling and Dietary Supplements are mandatory for new dietary  ingredients (and are used for premarket review of such ingredients) but  discretionary for other food (and are associated with postmarket review).   A unique characteristic of the hazard identification phase of risk  assessment in FDA is that, by statute, if there is an adequate study that  indicates a food additive can cause cancer in animals, that additive is  labeled as a carcinogen under the conditions of the study.  No additional  corroboration or weight-of-evidence analysis is required in such cases, and  there is no need to complete the other three risk assessment steps before  proceeding to a regulatory decision.  FDA’s CVM is permitted to allow the  use of carcinogenic drugs in food-producing animals under the DES  proviso of the Federal Food, Drug, and Cosmetic Act, as amended,  provided that “no residue of such drug will be found.”
OSHA’s Directorate of Health Standards Programs is primarily responsible  for conducting the agency’s chemical risk assessments.  Such assessments  focus specifically on the potential risks to workers associated with  exposures to chemicals in an occupational setting.  In contrast to agencies  regulating environmental exposures to toxic substances, OSHA frequently  has relevant human data available on occupational exposures.  Even when  the agency assesses risks based on animal data, OSHA said that the  workplace exposures of concern are often not far removed from levels  tested in the animal studies.  Therefore, OSHA’s risk assessments do not  extrapolate as far beyond the range of observed toxicity as might be  necessary to characterize environmental exposure risks.  OSHA’s risk  assessment procedures have also evolved to consider data from advanced  physiologically based pharmacokinetic (PBPK) models on the relationship  between administered doses and effective doses (i.e., the amounts that  actually reach a target organ or tissue).  However, PBPK models are  complicated and require substantial data, which may not be available for  most chemicals.  OSHA therefore developed a set of 11 criteria to judge  whether available data are adequate to permit the agency to rely on PBPK  analysis in place of administered exposure levels when estimating human  equivalent doses.
section_title: Risk Assessment Procedures at RSPA
paragraphs: The applicable risk assessment guidance for RSPA is generally documented  within broader DOT-wide guidance on conducting regulatory analyses and  also in materials describing the agency’s Hazardous Materials Safety  Program.  Because of the particular regulatory context in which it operates,  RSPA does not apply the NAS four-step paradigm for risk assessment used  by EPA, FDA, and OSHA.  RSPA is primarily concerned with potential risks  associated with the transportation of hazardous materials.  In particular, it  is concerned with short-term or acute health risks due to relatively high  exposures from unintentional release of hazardous materials.  For its  purposes, RSPA identifies chemicals as hazardous materials according to a  regulatory classification system that is harmonized with internationally  recognized criteria and EPA-defined hazardous substances.  This  classification system defines the type of hazard associated with a given  material according to chemical, physical, or nuclear properties (e.g.,  whether it is an explosive, a flammable liquid, or a poisonous substance)  that can make it dangerous in or near transporting conveyances.   Therefore, a chemical’s toxicity is only one of its characteristics of concern  to RSPA, rather than being the primary focus of analysis as in assessments  of the other three agencies.  The risk analyses by RSPA focus on identifying  the potential circumstances under which unintentional releases of  hazardous materials could occur during transit (e.g., due to transportation  accidents) and assessing their consequences and probability of occurrence.   Analysis of different modes (e.g., via truck, rail, or aircraft) and routes of  transportation is an important component of RSPA’s consequence and  probability analyses.  Through DOT databases, directly relevant data on  the incidence and severity of hazardous materials transportation accidents  are available to assist RSPA in identifying and analyzing hazard scenarios.
Appendices II through V provide more detailed descriptions of the standard  procedures for chemical risk assessments in each of the four selected  agencies.
section_title: Agencies’ Risk Assessment Procedures Often Include Precautionary Assumptions and Methods
paragraphs: Assumptions and methodological choices are an integral and inescapable  part of risk assessment.  They are often intended to address uncertainty in  the absence of adequate scientific data.  However, those assumptions and  methods may also reflect policy choices, such as how to address variability  in exposures and effects among different individuals and populations, or  particular contextual requirements.  To the extent that the four agencies  identified the specific reasons for selecting their major assumptions or  methods, they most often attributed their choices to an evaluation of  available scientific data, the precedents established in prior risk  assessments, or policy decisions related to their regulatory missions.   Agencies’ statements regarding the likely effects of their preferred  assumptions and methods most often addressed the extent to which the  default options would be considered precautionary.  Some of the major  assumptions and methodological choices of EPA, FDA, and OSHA address  similar issues and circumstances during the risk assessment process,  especially regarding assessment of a chemical’s toxicity.
subsections: section_title: Agencies’ Assumptions and Methodological Choices Vary
paragraphs: Agency procedural guidelines and officials we contacted during our review  identified a large number and wide variety of major assumptions and  methodological choices that they might use when conducting chemical risk  assessments, in the absence of information that would indicate the  particular assumption or method is not valid in a given case.  Some of these  assumptions and methodological choices were very broad (e.g., the  common assumption that, in the absence of evidence to the contrary,  substances that produce adverse health effects in experimental animals  pose a potential threat to humans).  Other assumptions and choices were  more specific, covering particular details in the analytical process (e.g.,  identifying the preferred options for extrapolating high dose-response  relationships to low doses). EPA and OSHA identified some of their choices  as the default assumptions and methods of their agencies.  FDA officials  said that their agency does not require the use of specific default  assumptions or risk assessment methods, but there are assumptions and  methods that typically have been used as standard choices in FDA risk  assessments.  Although assumptions are also needed in RSPA’s risk  assessments, RSPA officials said that they do not have any default  assumptions.  Instead, they said that their assumptions are specific to, and  must be developed as part of, each risk assessment.
Appendices II through V present detailed information on some of what the  agencies identified as their major assumptions and methodological choices  in chemical risk assessments.  The tables illustrate both the number and  variety of assumptions that agencies may use when conducting those  assessments.
The following sections summarize information that was available from the  four agencies’ procedures and related documents on (a) when the agencies  employ major assumptions and methods, (b) their reasons for selecting  these options, (c) the likely effects on risk assessment results of these  options, and (d) how they compare to the assumptions and choices used by  other agencies or programs in similar circumstances.  In some cases the  agencies’ documents did not contain this information, but there is no  requirement that the agencies do so.  Also, the reason for using a particular  assumption and its effect on risk assessment results can vary on a case-by- case basis, and therefore might not be addressed in general risk assessment  guidance.  Nevertheless, both NAS and the Presidential/Congressional  Commission recommended greater transparency regarding the procedures,  assumptions, and results of agencies’ risk assessments.  Also, as will be  discussed more fully later in this report, the agencies’ own risk  characterization policies and practices emphasize the value of such  transparency in communicating information about risk assessment  procedures and results.  Recent regulatory reform proposals considered by  Congress have had provisions requiring transparency in the use of  assumptions.
section_title: When Assumptions and Methods Are Used
paragraphs: As previously mentioned, NAS and the Presidential/Congressional  Commission have both emphasized that science cannot always provide  definitive answers to questions raised during a risk assessment.  For  example, in 1983, NAS identified at least 50 points during the course of a  cancer risk assessment when choices had to be made on the basis of  professional judgment, not science.  EPA’s guidelines similarly point out  that, because there is no instance in which a set of data on an agent or  exposure is complete, all risk assessments must use general knowledge  and policy guidance to bridge data gaps.  Except in the case of RSPA,  default or standard assumptions and methods may be used by agencies to  address these gaps in knowledge, and to encourage consistency in the  efforts of agencies’ risk assessors to address such basic issues as:  uncertainty in the underlying data, model parameters, or state of  scientific understanding of how exposure to a particular chemical could  lead to adverse effects;  variability in the potential extent of exposure and probability of adverse  effects for various subgroups or individuals within the general  population; and   statutory requirements (and the related general agency missions) to be  protective of public health and the environment (e.g., to set standards  with “an adequate margin of safety”).
However, agency risk assessors have considerable flexibility regarding  whether to use particular assumptions and methods, even when the agency  has default or standard options.  For example, EPA stated that its revised  guidelines for carcinogen risk assessment were intended to be both explicit  and more flexible than in the past concerning the basis for making  departures from defaults, recognizing that expert judgment and peer  review are essential elements of the process.  The Executive Director of  ORD’s Risk Assessment Forum pointed out that, although EPA’s guidelines  always permitted such flexibility, without detailed guidance on departing  from default assumptions there had been a tendency for analysts to not do  so. He also stated that when determining whether to use a default, the  decision maker must consider available information on an underlying  scientific process and agent-specific data, and that scientific peer review,  peer consultation workshops, and similar processes are the principal ways  of determining the strength of thinking and the general acceptance of these  views within the scientific community.  FDA officials emphasized that their  agency does not presume that there is a “best way” of doing a risk  assessment and does not require the use of a specific risk assessment  protocol or of specific default assumptions, but they are continually  updating procedures and techniques with the goal of using the “best  available science.”
Agencies identified assumptions and methodological choices throughout  the risk assessment process, and each of the first three steps in the process  can have its own set of issues and choices that risk assessors need to  address.  During hazard identification, agencies must make choices about  which types of data to use and what types of adverse effects and evidence  will be considered in their analyses.  For example, risk assessors need to  decide whether data on benign tumors should be used along with data on  malignant tumors as the basis for quantitative estimates of cancer risks, or  whether only data on malignant tumors should be used.  During dose- response assessment, agencies may need to make assumptions when  extrapolating effects from animals to humans (e.g., how to determine  equivalent doses across different species).  In particular, choices among  assumptions and methods are needed when estimating dose-response  relationships at doses that are much lower than those used in the scientific  studies that provided the data for quantitative analysis.  During exposure  assessments, assumptions might be needed to address issues such as when  exposures occur (e.g., in infancy or childhood versus as an adult), how long  exposures last (e.g., short versus long term and continuous versus  episodic), differences in exposures and effects for the population as a  whole versus those affecting subpopulations and individuals, and questions  about the concentration and absorption of chemical agents.  Assumptions  about human behavior also affect the relative likelihood of different  exposure scenarios.  For example, in assessing children’s residential  exposures to a pesticide, risk assessors might need to make assumptions  about how long children play in a treated area, the extent to which they are  wearing clothing, and potential hand-to-mouth exposure to treated soil,  among other factors.
section_title: Why Particular Assumptions and Methods Are Selected
paragraphs: Agencies generally indicated that they use their major assumptions and  methodological choices in risk assessments when professional judgments  or policy choices must substitute for scientific information that is not  available or is inconclusive.  We examined risk assessment guidance  documents and procedures in the four agencies to determine whether the  agencies stated a specific scientific or policy basis for their choices, as  recommended by NAS and the Presidential/Congressional Commission.  In  approximately three-quarters of the choices that we reviewed, the agencies  provided at least some rationale for the use of particular assumptions or  methods.  The reasons most commonly cited were (1) an evaluation of  available scientific data, (2) the precedents established in prior risk  assessments, and (3) policy decisions related to their regulatory mandates.   In some instances, the agencies cited more than one reason in support of  their choices.  For example, officials from FDA’s Center for Veterinary  Medicine said they assume that an adult weighs 60 kilograms when  converting an acceptable daily intake (ADI) to an intake level of residues in  food because of historical precedent and because this assumption should  protect women, growing adolescents, and the elderly.
Of the three reasons, the agencies most often cited their evaluation of  available scientific evidence as a reason for selecting particular  assumptions or analytical methods.  For example, one of the default  assumptions in EPA’s carcinogen risk assessment guidance is that positive  effects in animal cancer studies indicate that the agent under study can  have carcinogenic potential in humans.  EPA cited scientific research  supporting this assumption, such as the evidence that nearly all agents  known to cause cancer in humans are carcinogenic in animals in tests with  adequate protocols.  Other EPA guidelines stated that, in general, a  threshold is assumed for the dose-response curve for agents that produce  developmental toxicity.  EPA’s guidelines noted that this assumption is  based on the known capacity of the developing organism to compensate for  or repair a certain amount of damage at the cellular, tissue, or organ level.   OSHA cited scientific evidence and the views of the Office of Science and  Technology Policy on chemical carcinogenesis (the origin or production of  a tumor) to support its choice to combine data on benign tumors with the  potential to progress to malignancies with data on malignant tumors  occurring in the same tissue and the same organ site.
Even when basing a choice upon available scientific studies and data,  professional judgment may still be required regarding which particular  method or assumption to choose among competing alternatives.  The  scientific evidence might show a range of assumptions or methods that  provide plausible results and may, in specific cases, vary in terms of which  one best fits the available evidence.  For example, different mathematical  models can be used for estimating the low-dose effects of exposure to  suspected carcinogens.  A basic problem for risk assessors is that, while  the results produced by different models may be similar at higher doses,  the estimates can vary dramatically at the low doses that are of concern to  agency regulators.  One study of 5 dose-response models showed that all of  the models produced essentially the same dose-response curves at higher  doses, but the models’ estimates differed by 3 or 4 orders of magnitude  (values 1,000 to 10,000 times different) at lower doses.  Because the  mechanism of carcinogenesis is not sufficiently understood, none of the  mathematical procedures for extrapolation has a fully adequate biological  basis.  Furthermore, because of the limitations in the ability of toxicologic  or epidemiologic studies to detect small responses at very low doses, dose- response relationships in the low-dose range are practically unknowable.
Agencies can encounter similar problems in attempting to determine how  much of a chemical will produce the same effect in humans that was  observed in animals.  An interagency group of federal scientists that  studied this issue noted that, although many alternatives had been  developed for such cross-species scaling, and despite considerable study  and debate, “no alternative has emerged as clearly preferable, either on  empirical or theoretical grounds.”  The group noted further that the  various federal agencies conducting chemical risk assessments therefore  developed their own preferences and precedents, and this variation “stands  among the chief causes of variation among estimates of a chemical’s  potential human risk, even when assessments are based on the same data.”   For purposes of consistency in federal risk assessments, the group  recommended a method intermediate between the two methods most  commonly used by federal agencies, but reiterated that methodologies in  use “have not been shown to be in error.”
Other reasons cited by the agencies for selecting assumptions or methods  included the precedents established in prior risk assessments and policy  decisions related to their regulatory missions and mandates.  For example,  FDA officials said that their practice of using the most sensitive species and  sex when calculating the ADI of animal drug residues in food was based on  historical precedents dating back to at least 1954.  In other instances, FDA  said that its use of precautionary assumptions was based on the agency’s  statutory responsibility to ensure to a “reasonable certainty” that the public  will not be harmed.  Similarly, EPA guidelines pointed out that the default  assumptions used in the agency’s risk assessments were chosen to be  health protective because EPA’s overall goal is public health protection.   For example, EPA’s neurotoxicity guidelines said that a choice to use the  most sensitive animal species to estimate human risk “provides a  conservative estimate of sensitivity for added protection to the public.”
section_title: Effects of Agencies’ Assumptions and Methods on Risk Estimates
paragraphs: The agencies provided information in their guidelines on the likely effects  of using particular assumptions or methods in about half of the examples  that we reviewed.  When that information was provided, it was usually in  the context of whether and to what extent the agencies’ choices could be  considered precautionary.  In a number of cases, EPA and FDA  characterized their assumptions and methods as precautionary in that they  were intended to avoid underestimating risks in the interest of protecting  public health.  Such assumptions tend to raise an agency’s estimate of risk  and lower the levels of exposure that are of regulatory concern.   Precautionary assumptions and methodological choices were a common  component of programs that have “tiered” approaches for conducting risk  assessments (e.g., EPA’s Superfund and pesticides programs).  In these  tiered risk assessment approaches, agencies move from initial rough  screening efforts to increasingly more refined and detailed levels of  analyses.  The initial screening assessments will typically involve very  precautionary “upper-bound” or even “worst-case” assumptions to  determine whether there is cause for concern.  Successive tiers of  assessment, if deemed necessary, are characterized in agency documents  as more detailed and focused assessments that require more extensive data  and rigorous analysis.  For example, EPA indicated that its screening  assessments might well use precautionary upper-bound point estimates of  exposures (e.g., that a chemical is used on 100 percent of the eligible crop  and at the maximum permissible limit).  However, subsequent tiers of  assessments might refine those estimates through the use of probability  distributions of exposure parameters or the use of monitoring data on  actual exposures, when feasible.
OSHA and RSPA also use precautionary assumptions in certain parts of  their risk assessment procedures.  However, these agencies identified few  of their risk assessment assumptions and methods as precautionary.  In  fact, OSHA sometimes selected assumptions or methods that it explicitly  characterized as less precautionary than those used by other agencies in  similar circumstances.  For example, OSHA stated that its standard  approach to low-dose extrapolation can be much less precautionary than  EPA’s or FDA’s approaches because it tends to use central estimates of  potency rather than upper-bound confidence limits.  OSHA officials also  noted that the algorithm they use is less precautionary because it may lead  to models that are sublinear at low doses.
The effect on risk estimates of using any one assumption is likely to be less  significant than that of applying a series of assumptions while conducting a  risk assessment, particularly if the assessment is compounding a string of  largely precautionary assumptions.  As we previously pointed out,  assumptions and choices may be needed at many points during each step of  an agency’s analysis.  The agency’s policy may well be to use precautionary  choices at most, if not all, of those points, if adequate information is not  available to indicate that the precautionary choice is invalid in a specific  case.  The potential for such a string of precautionary assumptions is  illustrated by the set of standard choices identified by FDA for risk  assessments of carcinogenic animal drug residues in foods consumed by  humans. 1. Regulation is based on the target tissue site exhibiting the highest  potential for cancer risk for each carcinogenic compound.
2.
If tumors are produced at more than one tissue site, the minimum  concentration of the compound that produced a tumor is used. 3. Cancer risk estimates are generally based on animal bioassays, using  upper 95-percent confidence limits of carcinogenic potency.4. Low-dose extrapolation is done using a nonthreshold, conservative,  linear-at-low-dose procedure (i.e., assuming that there is no dose that  would not cause cancer and that effects vary in proportion to the  amount of the dose).
5.
It is assumed that the carcinogenic potency in humans is the same as  that in animals. 6. The concentration of the residue in the edible product is at the  permitted concentration. 7. Consumption is equal to that of the 90th percentile consumer. 8. All marketed animals are treated with the carcinogen. 9.
In the absence of information about the composition of the total  residue in edible tissue, assume that the entire residue is of  carcinogenic concern.
FDA’s description of its risk assessment procedures acknowledged that  these assumptions “result in multiple conservatisms” and stated that some  of these choices are likely to overestimate risk by an unknown amount  (although the fourth assumption could also underestimate risk by an order  of magnitude).  However, the agency also said that these assumptions are  prudent because of the uncertainties involved and cited its statutory  responsibility to ensure to a reasonable certainty that the public will not be  harmed.  It is important to keep in mind that the primary purposes for  preparing such assessments are to identify safe concentration levels in  edible tissues and residue tolerances (the amount permitted to remain on  food) for postmarket monitoring rather than to produce a general estimate  of the risk posed by use of the animal drug.
section_title: Comparison of Agencies’ Assumptions
paragraphs: Agency documents very rarely made direct comparisons of their  assumptions and methodological choices to those used by other agencies,  and there is no requirement that they do so.  Our review indicated that EPA,  FDA, and OSHA risk assessment procedures have many basic assumptions  in common—for example, that one can use results of animal experiments  to estimate risks to humans, and that most potential carcinogens do not  have threshold doses below which adverse effects would not occur.  There  are other default or standard assumptions and models in the three  agencies’ risk assessment procedures that are similar, but not identical.   For example, all three agencies employ a linear mathematical model for  low-dose extrapolation (in the absence of information indicating that a  linear model is inappropriate in a particular case).  However, the agencies  prefer different options in the details of fitting such models, such as the  point of departure to low doses.  EPA and FDA also consider similar, but  not identical, sets of uncertainty or safety factors when using the NOAEL  approach for noncancer risk assessments.  Finally, as the discussion above  regarding low-dose extrapolation illustrates, there are also instances in  which the agencies use different assumptions in similar circumstances.
Table 1 compares and contrasts some of the risk assessment assumptions  or analytical methods identified in the guidelines or other descriptive  documents of EPA, FDA, and OSHA for use under similar circumstances.   (Note that, for comparability, the examples in table 1 all focus on  carcinogen risk assessments based on animal studies, but the agencies’  major assumptions and methods are not limited to only carcinogen risk  assessments.  Note also that the “circumstances” listed in the table also  include that the assumption or method would be used in the absence of  data to the contrary.)
There appears to be some convergence in the agencies’ risk assessment  assumptions in at least one area where there had been significant  differences—their methods for cross-species dose scaling.  In the absence  of adequate information on differences between species, EPA’s standard  practice in carcinogenic risk assessments had been to scale daily  administered doses by body surface area, whereas FDA’s and OSHA’s  standard practice had been to scale doses by body weight.  Recently, the  agencies have either adopted, or consider as one of their options, the  expression of doses in terms of daily amount administered per unit of body  weight to the ¾ power.
All four of the agencies included in our review have also been incorporating  more complex analytical methods and models into their risk assessment  procedures.  Some of these methods (such as the use of probabilistic  analyses to provide distributions of exposure parameters) help to address  issues of uncertainty and variability in risk assessments and lessen the  need for some precautionary assumptions.  Other advances, such as the use  of PBPK models, can provide better insights into how and to what extent a  chemical might produce adverse effects in humans.  One outcome of the  integration of these methods into agencies’ procedures is a diminishing of  the traditional distinction between cancer and noncancer risk assessment  methods.  EPA, in particular, has noted that it is less likely to consider  cancer and noncancer endpoints in isolation as it develops and  incorporates more advanced scientific methods to measure and model the  biological events leading to adverse effects.  According to EPA, the science  of risk assessment is moving toward a harmonization of the methodology  for cancer and noncancer assessments.
The use of newer, more complex models and methods also opens up a new  range of choices and assumptions in the analysis—along with the potential  for risk estimates to diverge because of the different assumptions that  might be used.  For example, in its methylene chloride final rule OSHA  reported on the results of its analyses as well as risk assessments  submitted to OSHA by other risk assessors.  Although most of the risk  assessments used a linearized multistage model to predict risk, there were  differences in the estimates produced by these assessments.  OSHA  pointed out that the differences in risk estimates were not generally due to  the dose-response model used, but to whether the risk assessor used PBPK  modeling to estimate target tissue doses and what assumptions were used  in the PBPK modeling.
Appendices II through V present more detailed information on some of the  major assumptions and methodological choices in each of the four selected  agencies.
section_title: Risk Characterization Policies and Practices Emphasize Transparency
paragraphs: In the risk characterization step of a risk assessment, agencies bring  together the results of the preceding analyses in the form of estimates and  conclusions about the nature and magnitude of a potential risk.  Agencies’  risk characterizations play a crucial role in explaining to decision makers  and other interested parties what the agency’s risk assessors have  concluded and on what basis they reached those conclusions.  Both EPA  and DOT have agencywide written policies on risk characterization that  emphasize the importance of providing comprehensive and transparent  characterizations of risk assessment results.  Although FDA and OSHA do  not have written risk characterization policies, officials of those agencies  pointed out that, in practice, they also tend to emphasize comprehensive  characterizations of risk assessment results, discussions of limitations and  uncertainties, and disclosure of the data and analytic methodologies on  which the agencies relied.
EPA’s program offices are generally responsible for completing risk  characterizations, and EPA’s agencywide guidance on this issue includes a  risk characterization policy, a guidance memorandum, and a handbook.   EPA’s policy stipulates that risks should be characterized in a manner that  is clear, transparent, reasonable, and consistent with other risk  characterizations of similar scope.  EPA said that all assessments “should  identify and discuss all the major issues associated with determining the  nature and extent of the risk and provide commentary on any constraints  limiting fuller exposition.”  EPA’s policy documents also recommend that  risk characterization should (1) bridge the gap between risk assessment  and risk management decisions; (2) discuss confidence and uncertainties  involving scientific concepts, data, and methods; and (3) present several  types of risk information (e.g., a range of exposures and multiple risk  descriptors such as high-end estimates and central tendencies).  It is also  EPA’s policy that major scientifically and technically based work products  related to the agency’s decisions normally should be peer-reviewed.
In its guidelines for carcinogen risk assessment, EPA also suggests  preparing separate “technical” characterizations to summarize the findings  of the hazard identification, dose-response assessment, and exposure  assessment steps.  The agency’s risk assessors are then to use these  technical characterizations to develop an integrative analysis of the whole  risk case, followed by a less extensive and nontechnical summary intended  to inform the risk manager and other interested readers.  EPA identified  several reasons for preparing separate characterizations of each analysis  phase before preparing the final integrative summary.  One is that different  people often do the analytical assessments and the integrative analysis.   The second is that there is very often a lapse of time between the conduct  of hazard and dose-response analyses and the conduct of the exposure  assessment and integrative analysis.  Thus, according to EPA, it is  necessary to capture characterizations of assessments as the assessments  are done to avoid the need to go back and reconstruct them.  Finally,  several programs frequently use a single hazard assessment for different  exposure scenarios.
DOT’s policy principles regarding how the results of its risk or safety  assessments should be presented are straightforward and encourage  agency personnel to:   make public the data and analytic methods on which the agency relied  (for replication and comment);   state explicitly the scientific basis for significant assumptions, models,  and inferences underlying the risk assessment, and explain the rationale  for these judgments and their influence on the risk assessment;  provide the range and distribution of risks for both the full population at  risk and for highly exposed or sensitive subpopulations and encompass  all appropriate risk to health, safety, and the environment;  place the nature and magnitude of risks being analyzed in context  (including appropriate comparisons to other risks); and  use peer review for issues with significant scientific dispute.
FDA does not have a written risk characterization policy, but FDA officials  said that, in practice, the agency uses a standard approach that is similar to  EPA’s official policy.  They said that FDA’s general policy is to reveal the  risk assessment assumptions that have the greatest impact on the results of  the analysis, and to state whether the assumptions used in the assessment  were conservative.  FDA officials also said that their risk assessors attempt  to show the implications of different distributions and choices (e.g., the  results expected at different levels of regulatory intervention).  FDA may  employ probabilistic methods, such as Monte Carlo analysis, to provide  additional information on the effects of variability and uncertainty on  estimates of risk, and there are some differences in FDA risk  characterization procedures depending on the products being regulated  and the nature of the risks involved.
Although OSHA does not have written risk characterization policies, in  recent rules the agency emphasized (1) comprehensive characterizations of  risk assessment results; (2) discussions of assumptions, limitations, and  uncertainties; and (3) disclosure of the data and analytic methodologies on  which the agency relied. The agency devoted considerable effort to  addressing uncertainty and variability in its risk estimates.  Such efforts  included performing sensitivity analyses and providing estimates produced  by alternative analyses and assumptions (including analyses by risk  assessors outside of OSHA).  In its risk characterizations, OSHA provided  both estimates of central tendency and upper limits (such as the 95th  percentile of a distribution).
Appendices II through V provide more detailed descriptions of the risk  characterization policies or approaches of each of the four selected  agencies.
section_title: Conclusions
paragraphs: Risk assessment is an important, but extraordinarily complex, element in  federal agencies’ regulation of potential risks associated with chemicals.   The assessments can help agencies decide whether to regulate a particular  chemical, select regulatory options, and estimate the benefits associated  with regulatory decisions.  Scientific studies in such areas as toxicology  and epidemiology are often used to produce the information needed for  risk assessment decisions.  However, assessors frequently must produce  estimates of risk without complete scientific information about the extent  of exposures to potentially hazardous substances and the effects of those  exposures on human health and safety or the environment.  Therefore,  professional judgment with regard to assumptions and methodological  choices is an inherent part of conducting risk assessments.  The  appendices to this report identify many of the major assumptions and  methods that can be used in risk assessments prepared for EPA, FDA,  OSHA, and RSPA.  The number and variety of those assumptions and  methods illustrate the range of issues that risk assessors confront during  the course of their analyses.
Although there were more similarities than differences in the general risk  assessment procedures of three of the four agencies, there were also some  notable differences in the agencies’ specific approaches, methods, and  assumptions.  These differences can significantly affect the results and  conclusions drawn from the assessments.  Therefore, risk estimates  prepared by different agencies, or by different program offices within those  agencies, may not be directly comparable, even if the same chemical agent  is the subject of the risk assessment.  In some cases, the reasons for those  differences are readily apparent, such as when agencies focus on different  types of adverse effects (e.g., cancer versus noncancer) or different types  and sources of exposure.  For example, the same chemical (e.g., methylene  chloride) might be identified as a significant hazard by one agency in one  exposure setting (OSHA for occupational exposures) but as a low hazard  by another agency in a different setting (EPA for Superfund hazard ranking  screening).  In other cases, the reasons for different estimates may be more  subtle and harder to discern within the many layers of analyses and  professional judgments used to prepare the risk assessment.
Because of the range of assumptions and methods that are scientifically  plausible in a given situation, the risk characterization phase of the risk  assessment process takes on added importance.  In their risk  characterization policies or procedures, the four agencies acknowledge the  importance of clearly communicating not only their conclusions about the  nature and likelihood of a given risk but also disclosing (1) the  assumptions, methods, data, and other choices that had the greatest impact  on risk estimates; (2) why those choices were made; and (3) the effect that  alternative choices would have had on the results of a risk assessment.   Transparency is important with regard to both individual risk assessments  and in agencies’ general procedures regarding how the assessments should  be conducted.  Those procedures encourage consistency in how agencies  conduct risk assessments and provide insights into agencies’ decision  making when analyzing risks.  For example, frameworks delineated by EPA  and OSHA for departing from certain default assumptions inform both  agency personnel and external parties as to whether particular data or  analyses are acceptable to the agency.
Our review focused on describing the framework for agencies’ chemical  risk assessments.  We did not evaluate how that framework is applied in  practice, or how risk assessment results affect risk management decisions  by agencies and other policymakers.  Nevertheless, our report highlights  the value of policymakers and other interested parties becoming aware of  the underlying risk assessment context, procedures, assumptions, and  policies when using risk assessment data for risk management and other  public policy decisions.  For example, prudent use of risk data requires the  user to be aware of the extent to which the data:  represent estimates from screening assessments (which may rely  heavily on precautionary assumptions) or estimates from subsequent,  more rigorous assessments (which are likely to rely on more detailed  and case-specific data and analyses);  show the distribution of exposures and potential adverse effects across  the population, including the extent to which the data address risks of  the most exposed or sensitive subgroups of the population, or focus on  only part of that distribution;  were produced using directly relevant scientific data that were available  or had to rely on general assumptions and models; and  reflect the flexibility permitted in agencies’ standard procedures or  guidelines to depart from past precedent and default choices to use  alternative assumptions and models, when appropriate.
In our review we also found that, although the underlying statutes specified  the use of particular methods or assumptions in only three instances, the  legal and situational context within which an agency is conducting a  chemical risk assessment has a major effect on the specific focus, scope,  and level of detail of the resulting assessment.  Comparison of risk  assessment estimates from different agencies and programs therefore  requires careful consideration of these contextual differences.
Because the central purpose of our review was to describe the framework  for selected agencies’ chemical risk assessments, rather than to evaluate  and critique how that framework is applied in practice, we are not making  any recommendations in this report.
section_title: Agency Comments and Our Evaluation
paragraphs: At the end of our review, we sent a draft of this report to five experts in the  field of risk assessment to ensure the technical accuracy of the report.  The  three experts who provided comments were (1) the Executive Director of  the Presidential/Congressional Commission, (2) the individual who  prepared the Survey of Methods for Chemical Health Risk Assessment  Among Federal Regulatory Agencies for the Commission, and (3) an  expert in risk assessment at Resources for the Future.  The experts  generally indicated that the report had no material weaknesses, but  provided a number of technical suggestions that we incorporated as  appropriate.  For example, two of the reviewers suggested that the report’s  discussion of the NAS four-step risk assessment paradigm, although  reflecting the definitions generally relied upon by federal agencies, should  also identify an updated view regarding the concept of risk  characterization.  The updated view is that risk characterization should be  a decision-driven activity performed as part of the risk management  decision making process rather than a stand-alone activity at the end of a  risk assessment. We included this perspective in the report’s background  section.
During our review, we obtained technical comments from officials in each  of the four agencies on a draft of the appendices to this report, which we  incorporated as appropriate.  On June 18, 2001, we sent a draft of the full  report to the Secretaries of Health and Human Services, Labor, and  Transportation, and the Administrator of EPA for their review and  comment.  None of the agencies provided formal comments on the report,  but we received additional technical comments and suggestions from all  four of the agencies, which we incorporated as appropriate.
As arranged with your office, unless you publicly announce the contents of  this report earlier, we plan no further distribution until 30 days after the  date of this report. At that time, we will send copies of this report to the  Ranking Minority Member, House Committee on Energy and Commerce;  the Ranking Minority Member, Subcommittee on Environment and  Hazardous Materials, House Committee on Energy and Commerce; the  Secretaries of Health and Human Services, Labor, and Transportation; and  the Administrator of EPA.  We will also make copies available to others on  request.
If you have any questions concerning this report, please call me or Curtis  Copeland at (202) 512-6806.  Key contributors to this assignment were  Timothy Bober and Aaron Shiffrin.
section_title: Objectives, Scope, and Methodology
subsections: section_title: Scope and Objectives
paragraphs: As requested, our review focused on the chemical risk assessment  procedures, assumptions, and policies of four federal agencies with  responsibilities for regulating or managing risks from potential exposure to  chemicals—the Environmental Protection Agency (EPA), the Food and  Drug Administration (FDA) within the Department of Health and Human  Services (HHS), the Occupational Safety and Health Administration  (OSHA) within the Department of Labor, and the Department of  Transportation’s (DOT) Research and Special Programs Administration  (RSPA—in particular the Office of Hazardous Materials Safety).  Our  specific objectives were to identify and describe (1) the general context for  the agencies’ chemical risk assessment activities; (2) what the agencies  view as their primary procedures for conducting risk assessments; (3) what  the agencies view as the major assumptions or methodological choices in  their risk assessment procedures; and (4) the agencies’ procedures or  policies for characterizing the results of risk assessments.  To the extent  feasible, we were also asked to identify for the assumptions and choices  identified in the third objective (a) at what stages of the risk assessment  process they are used, (b) the reasons given for their selection, (c) their  likely effects on risk assessment results, and (d) how they compare to the  assumptions and choices used by other agencies or programs in similar  circumstances.
section_title: Methodology
paragraphs: To address our objectives, we relied primarily on a detailed review and  analysis of agencies’ general guidance documents on chemical risk  assessment or, if there were no guidance documents, reviews of specific  examples of agency risk assessments.  We supplemented that information  with material from secondary source reports on risk assessment and  interviews with agency officials.  Among the secondary sources that we  used were relevant reports by the Congressional Research Service,  National Academy of Sciences (NAS), and the Presidential/Congressional  Commission on Risk Assessment and Risk Management (hereinafter  referred to as the Presidential/Congressional Commission).  In particular,  as a starting point for our review we used a report on federal agencies’  chemical risk assessment methods that was prepared by Lorenz Rhomberg  for the Presidential/Congressional Commission.  That report provided the  baseline descriptions of some of the chemical risk assessment procedures  at EPA, FDA, and OSHA.  We asked officials of those agencies to review  Rhomberg’s report to identify information that was still relevant to  addressing the objectives of this report as well as information that they felt  should be revised or added to reflect the agencies’ current procedures.
There are several important limitations to our review.  First, chemical risk  assessment is just one of several types of risk assessment being conducted  in federal agencies.  Therefore, our review cannot be used to characterize  other types of risk assessments (e.g., risks associated with radiation  exposure).  In fact, FDA officials considered risk assessments related to the  human drug approval process to be outside the scope of our review  because a completely different protocol is used in those assessments.   However, limiting the scope of our review to chemical risk assessments  makes comparisons among the agencies included more relevant and  meaningful.  Second, our review did not include all agencies or programs  that conduct risk assessments involving chemicals.  For example, we did  not include the Consumer Product Safety Commission, which periodically  assesses products with potential risks from chemicals.  Nor did we include  the Agency for Toxic Substances and Disease Registry, which prepares  “health assessments” that closely resemble risk assessments but has no  regulatory authority.  We focused on the risk assessment procedures in four  federal agencies that regularly conduct chemical risk assessments in  support of regulatory activities and/or could illustrate the diversity of risk  assessment procedures.  However, the results of our review cannot be  considered representative of chemical risk assessments in all federal  agencies.  Third, our review does not describe every chemical risk  assessment procedure or assumption used by the agencies we reviewed.   The material describing the agencies’ procedures is both voluminous and  extremely complex.  The detailed information that we provide on agency  assumptions is illustrative of the assumptions included in agencies’  procedures, but not a compendium of all such assumptions.  In addition,  we concentrated primarily on the human health and safety risk assessment  procedures of the four agencies and, to a lesser extent, on ecological risk  assessment procedures.  Fourth, this report describes agencies’ general  procedures and policies, but it is not a compliance review of how well  those procedures and policies are applied with regard to individual  assessments.  The agencies’ guidelines represent suggested procedures and  are not binding, so the agencies’ practices may justifiably vary from the  general frameworks we describe.  In practice, risk assessments do not  follow a simple recipe or formula.  Each assessment has unique issues or  characteristics that require case-specific resolutions.  Finally, this report  does not address risk management issues—e.g., using the results of a risk  assessment to determine what level of exposure to a risk agent represents  an acceptable or an unacceptable risk and deciding what control options  should be used.
We conducted this review between February 2000 and March 2001 in the  Washington, D.C., headquarters offices of the selected agencies in  accordance with generally accepted government auditing standards.  We  obtained technical comments on our descriptions of the agencies’  procedures, assumptions, and policies in the appendices from  knowledgeable agency personnel.  We then provided the draft report to  external experts in risk assessment, including the Center for Risk Analysis  at the Harvard School of Public Health in Boston, MA; Resources for the  Future in Washington, D.C.; the Executive Director of the  Presidential/Congressional Commission; and Lorenz Rhomberg, the analyst  who surveyed federal agencies’ chemical risk assessment procedures for  the Commission. After incorporating their comments, we provided a draft  of this report to the Secretaries of Health and Human Services, Labor, and  Transportation; and the Administrator of the Environmental Protection  Agency for their review and comment.
section_title: Organization of Appendices on Chemical Risk Assessment at Selected Federal Agencies
paragraphs: In the following appendices, we provide more detailed information  regarding the framework and methods applicable to chemical risk  assessment activities of EPA, FDA, OSHA, and RSPA.  There is a separate  technical appendix covering each of these four agencies, along with their  relevant offices, programs, or centers that are involved in conducting  chemical risk assessments.
For consistency and ease of presentation, we have generally organized the  appendices on each agency according to a standard format with four major  sections.  1. We describe the general context for the chemical risk assessment  activities of each agency.  This includes a summary of the primary risk  statutes, mandates, and tasks related to potential risks from exposure  to chemical agents. 2. We identify and summarize the standard risk assessment procedures of  each agency and, if applicable, each agency’s various offices, programs,  or centers.  This section is generally organized by the major analytical  steps of the risk assessment process: hazard identification, dose- response assessment, and exposure assessment.  These correspond to  the first three steps of the four-step paradigm for risk assessment as  defined by NAS and used by three of the four agencies covered by our  review.  (We address the fourth step of the process, risk  characterization, as a separate objective in the final section of each  agency appendix.) Within the descriptions of those steps, we often  distinguish between the procedures used for assessing cancer and  noncancer effects.  Given developments in risk assessment methods,  these distinctions are sometimes more artificial than real.3. We present additional information about major assumptions and  methodological choices in the agencies’ standard risk assessment  procedures.  For EPA, FDA, and OSHA, the primary focus of this  section is a detailed table identifying some of the major agencywide or  program-specific assumptions that may be used in chemical risk  assessments.  To the extent that such information was available, each  of these tables also includes information on the agency’s reason(s) for  selecting a particular assumption, when in the risk assessment process  the agency would apply the assumption, and the likely effect of using  the assumption on risk assessment results.  (Because agencies very  rarely made direct comparisons of their choices to those of other  agencies in their risk assessment guidelines or related documents, we  have not included a separate column on that topic in the appendix  tables.  That objective is, however, addressed in the letter portion of  this report.)  The appendix on RSPA does not include all of these  elements because of differences in its context and approach to  chemical risk assessment. 4. The final section of each appendix addresses each agency’s approach  or policies for characterizing the results of risk assessments for agency  decision makers and other interested parties.  In particular, we describe  the agency’s policies or practices with regard to the transparency of  risk assessment results, such as reporting the range and distribution of  risks and identifying the uncertainties in the risk analysis and  underlying data.
To avoid repetition in the appendices on agencies’ risk assessment  procedures, our most detailed descriptions of basic methods and issues  appear in the EPA appendix under the discussion of agencywide  procedures.  Descriptions of procedures used by other agencies or  programs, including the individual program offices within EPA, then  reference the EPA-wide descriptions of those particular methods, if they  are similar.
Although we provide much more detailed technical information in these  appendices than in the main body of the report, it is still important to  recognize that agencies’ risk assessment methods are more involved and  complex than we have described in this report.  In particular, the tables of  assumptions do not represent a comprehensive listing of all assumptions  and choices of the agencies.  Agencies might use many different types and  numbers of assumptions in any given assessment, and the assumptions are  being altered over time to reflect scientific improvements and changes in  risk approaches and the regulatory context.  However, the information  presented is intended to illustrate the types and diversity of procedures and  assumptions employed by the agencies we examined.
section_title: Chemical Risk Assessment at the Environmental Protection Agency
paragraphs: Chemical risk assessment at the Environmental Protection Agency (EPA) is  a complex and diverse undertaking.  The variety and range of the relevant  regulatory authorities and activities has a major effect on the organization  and conduct of risk assessment at the agency.  An expanding set of agency  guidelines reflects the evolving nature of EPA’s risk assessment  procedures.  EPA generally follows the four-step risk assessment process  identified by the National Academy of Sciences (NAS).  Changes are  occurring in EPA’s approaches to cancer, noncancer, and exposure  assessments, with a general trend toward the development and application  of more complex and comprehensive methodologies.  To a greater extent  than the other agencies we reviewed, EPA has established a set of default  assumptions (often precautionary in nature) and standard data factors for  use by its risk assessors.  In the “tiered” risk assessment approaches  commonly employed by EPA’s program offices, precautionary default  assumptions are most often used during initial screening assessments,  when the primary task generally is to determine whether a risk might exist  and more rigorous analysis is needed.  However, the information necessary  for more detailed analysis is not always available, so for regulatory  purposes the agency may be limited to using results from its initial tiers of  risk assessments.  In presenting the results of its risk assessments, it is  EPA’s policy that risk characterizations should be prepared in a manner  that is clear, transparent, reasonable, and consistent with other risk  characterizations of similar scope prepared across the programs in the  agency.
The following sections describe for EPA and its component offices, the  context for chemical risk assessment, the general procedures for  conducting risk assessments, major assumptions and methodological  choices in those procedures, and the agency’s policy for risk  characterization.  Because chemical risk assessment at EPA is such a  complex and diverse activity, this appendix can only summarize and  illustrate the range of contexts, procedures, assumptions and methods, and  policies that affect the conduct of EPA risk assessments.  For example, as  in our report as a whole, this appendix focuses primarily on human health  and safety risk assessment and less on ecological risk assessment.   However, we have included a brief section on EPA’s ecological risk  assessment guidelines under our discussion of agencywide risk assessment  procedures and illustrated the role played by ecological risk assessment in  the risk assessment activities of some, but not all, of EPA’s program offices  under our discussion of program-specific procedures.  As a practical  matter, this appendix reflects risk assessment topics that were addressed  in agencywide or program-specific guidelines or descriptions of chemical  risk assessment at EPA.  To the extent that such activities were not  explicitly addressed in the agency’s risk assessment guidelines and related  documents, there may be little information on them in this appendix.
subsections: section_title: Context for EPA Chemical Risk Assessment
paragraphs: EPA is responsible for a wide range of regulatory—and related risk  assessment—activities pertaining to potential health, safety, and  environmental risks associated with chemical agents.  This range of  activities reflects an equally broad and diverse range of underlying  environmental statutes.  According to EPA, close to 30 provisions within  the major environmental statutes require decisions based on risk, hazard,  or exposure assessment, with varying requirements regarding the scope  and depth of the agency’s analyses.  In general, EPA’s regulatory authority  regarding chemical agents is compartmentalized according to the various  kinds and sources of exposure—such as pesticides, drinking water  systems, or air-borne pollutants—and reflected in the agency’s organization  into various program offices—such as the Office of Air and Radiation,  Office of Solid Waste, and Office of Water.  Table 2 summarizes the  principal statutes, regulatory tasks, and risk mandates associated with  chemical risk assessment activities of EPA’s offices.
A number of other contextual factors affect the extent of involvement by  EPA offices in assessing and using risk assessment information in support  of the various statutes, mandates, and tasks identified in table 2.
Risk assessment information may not be the only, or even the primary,  basis for the ultimate risk management decision.  EPA statutes vary  fundamentally by whether the basis for regulation is (1) risk (health and  environmental) only, (2) technology-based, or (3) risk balancing  (consideration of risks, costs, and benefits).
For some chemical risk assessment activities, EPA has a secondary role.
Instead, the main responsibility for determining the relative risk of a  chemical, compiling and analyzing risk-related data, or completing other  tasks associated with a particular statute might lie with industry, states,  or local entities.
In practical terms, the resources available for conducting a risk  assessment for a given chemical might limit the depth and scope of  EPA’s (or other parties’) analysis.  Such resource limitations might  include not only schedule and staffing constraints, but often the amount  and quality of directly relevant scientific data available for analysis.
Risk assessment activities involve both EPA’s program offices and its Office  of Research and Development (ORD), which is the principal scientific and  research arm of the agency.  ORD often does risk assessment work for EPA  program offices that focuses on the first two steps in the four-step NAS  process—hazard identification and dose-response assessment—in  particular, the development of “risk per unit exposed” numbers.  The  exposure assessment and risk characterization steps tend to be the  responsibility of the various regulatory programs at EPA.  However,  according to agency officials, both program offices and ORD may conduct  all of the risk assessment steps in particular cases.  For example, OW’s  Office of Science and Technology does all of the assessments for purposes  of the SDWA, and, because of their particular statutory mandates, OPP and  OPPT have developed the capability to conduct all steps of a risk  assessment on their own.  ORD carries out all steps of highly complex,  precedent-setting risk assessments of specific chemicals, such as dioxin  and mercury.
ORD also helps to coordinate the development of EPA’s risk assessment  methods, tools, models, and policies.  In particular, much of EPA’s  agencywide guidance on conducting risk assessments is developed and  disseminated through ORD, with input from EPA’s program offices, Science  Policy Council, and Science Advisory Board, as well as other external  parties.  Coordination of risk assessment activities also occurs through  EPA’s Risk Assessment Forum and the agency workgroups that approve  information for entry into EPA’s Integrated Risk Information System (IRIS).   The Risk Assessment Forum is a standing committee of senior EPA  scientists that was established to promote agencywide consensus on  difficult and controversial risk assessment issues and to ensure that this  consensus is incorporated into appropriate EPA risk assessment guidance.   Managed by ORD, IRIS is a computerized database that contains  information on human health effects that may result from exposure to  various chemicals in the environment.  IRIS was initially developed for EPA  staff in response to a growing demand for consistent information on  chemical substances for use in risk assessments, decision making, and  regulatory activities.  The entries in IRIS on individual chemicals represent  a consensus opinion of EPA health scientists representing the program  offices and ORD and have been subject to EPA’s peer review policy since its  issuance in 1994.
section_title: Risk Assessment Procedures
paragraphs: There are agencywide risk assessment procedures that EPA’s various  program offices generally follow, but each office also has different  statutory mandates and risk assessment tasks associated with its  regulatory authority.  These contextual differences contribute to some  program-specific variations in the conduct of chemical risk assessments.   In addition, EPA’s procedures are in transition from more simplistic  traditional methods for identifying and assessing risks to increasingly  complex models and methods.  It is particularly important to recognize  that, while most EPA guidelines (and this appendix) distinguish between  cancer and noncancer procedures, this distinction is becoming increasingly  blurred as new scientific methods are being developed and applied.  In  general, EPA follows the NAS four-step process for human health risk  assessments: (1) hazard identification, (2) dose-response assessment,  (3) exposure assessment, and (4) risk characterization.  However, for  ecological risk assessment, EPA’s guidelines recommend a three-step  process: (1) problem formulation, (2) analysis, and (3) risk  characterization.
subsections: section_title: Guidelines
paragraphs: To a much greater extent than the other agencies we reviewed, EPA has  documented its risk assessment procedures and policies in a voluminous  and expanding set of guidelines, policy papers, and memoranda.  These  documents are primarily intended as internal guidance for use by risk  assessors in EPA and those consultants, contractors, or other persons who  perform work under EPA contract or sponsorship.  However, the  documents also make information on the principles, concepts, and  methods used in EPA’s risk assessments available to other interested  parties.  EPA’s guidelines undergo internal and external peer review.
Beginning in 1986, EPA published a series of risk assessment guidelines to  set forth principles and procedures to guide EPA scientists in the conduct  of agency risk assessments, and to inform agency decision makers and the  public about these procedures.  In general, EPA adopted the guiding  principles of fundamental risk assessment works, such as the 1983 Red  Book by the NAS’ National Research Council (NRC).  EPA’s guidelines  supplement these principles.  Five sets of guidelines were finalized in 1986,  including guidelines for carcinogen risk assessment, mutagenicity risk  assessment, health risk assessment of chemical mixtures, health  assessment of suspect developmental toxicants, and estimating exposures.   In part to respond to advances and changes in risk assessment methods— but also in response to criticisms of its guidelines by NRC, among others— EPA has revised most of these guidelines, in either proposed or final form,  and produced additional guidance documents.
Statutory changes have also prompted revisions and expansions of EPA’s  risk assessment guidelines and policy papers.  In the Clean Air Act  Amendments of 1990, for example, Congress directed EPA to revise its  carcinogen risk assessment guidelines, taking into consideration the NAS  recommendations, before making any determinations of the “residual  risks” associated with emissions of hazardous air pollutants.  The results  of the NAS study appeared in the 1994 NRC report, Science and Judgment  in Risk Assessment.  Among other things, NRC recommended that EPA  better identify the inference (default) assumptions in its guidelines, explain  the scientific or policy bases for selecting them, and provide guidance on  when it would be appropriate to depart from the assumptions.
The current set of agencywide risk assessment guidelines and policies  includes the following major topics: carcinogen risk assessment,  neurotoxicity risk assessment,  reproductive toxicity risk assessment,  developmental toxicity risk assessment,  mutagenicity risk assessment,  health risk assessment of chemical mixtures,  guidelines for exposure assessment,  guidelines for ecological risk assessment,  other risk assessment tools and policies,  probabilistic analysis in risk assessment,  use of the benchmark dose approach in health risk assessment,  reference dose (RfD) and reference concentration (RfC),  evaluating risk to children, and  EPA risk characterization program.
In addition to these agencywide documents, there are also numerous  program-specific guidelines and policy documents.  For example, the Risk  Assessment Guidance for Superfund series covers various stages of  human health evaluation as well as ecological risk assessment and  probabilistic risk assessment.  There are also guidelines and policy  memoranda at the headquarters and regional office level that supplement  these general Superfund guidelines.  Similarly, OPP, with input from ORD,  has developed a series of science policy papers specifically on issues  related to pesticide risk assessments, in response to provisions of the Food  Quality Protection Act of 1996.
Describing EPA’s risk assessment procedures with any certainty is a  difficult task, given the sheer volume of EPA guidance documents, the  continuing evolution of risk assessment practices, and the extent to which  many of EPA’s revisions are currently draft in nature.  For example, the  official guidelines for cancer risk assessment are still the 1986 version, but  the agency published a proposed revision of those guidelines in 1996, and  continued to revise them in 1999, but the revised guidelines have not yet  been made final by EPA.  Although the various revisions since 1986 do not  represent official agency policy at this stage, the approaches that they  describe are likely to provide a more accurate reflection of current  practices and directions in EPA risk assessments.  To some extent EPA is  already applying these newer approaches, for example in the Office of  Water’s revised methodology for deriving ambient water quality criteria for  the protection of human health and the Office of Pesticide Programs’  Cancer Peer Review Committee.
section_title: Agencywide Risk Assessment Procedures
paragraphs: The following sections summarize the basic elements of EPA’s agencywide  procedures for conducting risk assessments.  Because most of EPA’s  guidelines focus on human health risks, this section also focuses primarily  on health assessments in describing EPA’s general approach.  EPA  generally uses the NAS four-step process for those assessments.  However,  a separate short section on EPA’s approach to ecological risk assessment  appears at the end of this agencywide summary.  Also, while this appendix  (and most of the source material from which it was derived) discusses  procedures for assessing cancer and noncancer effects separately, this  distinction is increasingly artificial.  As EPA noted in its Strategy for  Research on Environmental Risks to Children, the agency is less likely to  consider cancer and noncancer endpoints in isolation as it develops and  incorporates more advanced scientific methods to measure and model the  biological events leading to adverse effects.  According to EPA, the science  of risk assessment is moving toward a harmonization of the methodology  for cancer and noncancer assessments.
subsections: section_title: Hazard Identification
paragraphs: EPA’s approach to hazard identification changed significantly between the  agency’s 1986 guidelines and its proposed revision.  In its 1986 guidelines,  EPA defined a hierarchical classification scheme for hazard identification  of chemical agents (see table 3).  In this scheme, analysis of whether an  agent is a potential human carcinogen proceeds through distinct steps  based on the type of human, animal, or “other” evidence available and its  quality (whether such evidence is sufficient, limited, or inadequate),  resulting in classification of the agent in one of six alphanumeric  categories.
In response to further developments in the understanding of  carcinogenesis, and to address limitations of its 1986 scheme, EPA  proposed a revised approach that melds the separate human-animal-other  processes into a single comprehensive evaluation.  In this approach,  weighing the evidence and reaching conclusions about the carcinogenic  potential of an agent would be accomplished in a single step after assessing  all individual lines of evidence.  Compared to the 1986 guidelines, the  proposed revision also encourages fuller use of all biological information— instead of relying primarily on tumor findings—and emphasizes analysis of  the agent’s mode of action in leading to tumor development. “Mode of action” is defined as a series of key events and processes, starting with  interaction of an agent with a cell and proceeding through operational and anatomical  changes resulting in cancer formation.
EPA starts with a review and assessment of the toxicological database to  identify the type and magnitude of possible adverse health effects  associated with a chemical.  Exposure to a given chemical might result in a  variety of toxic effects, so EPA has produced separate guidelines for the  assessment of mutagenicity, developmental toxicity, neurotoxicity, and  reproductive toxicity.  However, assessments for these noncancer health  effects may also overlap.  For example, developmental effects might be  traced to exposures and factors also covered by reproductive toxicity  assessments, and developmental exposures may result in genetic damage  that would require evaluation of mutagenicity risks.  The EPA guidelines  for noncancer effects are not step-by-step manuals, and they do not  prescribe a hazard identification classification scheme.  Instead, they focus  on providing general advice to risk assessors on different types of toxicity  tests or data and on the appropriate toxicological interpretation of test  results (e.g., which outcomes should be considered adverse effects).
In addition to considering the types and severity of potential adverse  effects, hazard identification would also consider and describe the nature  of exposures associated with these effects.  A review of the full range of  possibilities would consider:  acute effects—generally referring to effects associated with exposure to  one dose or multiple doses within a short time frame (less than 24 hours,  for example);  short-term effects—associated with multiple or continuous exposure  occurring within a slightly longer time frame, usually over a 14-day to 28- day time period;  subchronic effects—associated with repeated exposure over a limited  period of time, usually over 3 months; and  chronic effects—associated with continuous or repeated exposure to a  chemical over an extended period of time or a significant portion of the  subject’s lifetime.
Procedurally, there is an important variation from the distinct four steps of  the risk assessment paradigm.  In its guidelines, EPA notes that its normal  practice for assessments of noncancer health effects is to do hazard  identification in conjunction with the analysis of dose-response  relationships.  This is because the determination of a hazard is often  dependent on whether a dose-response relationship is present.  According  to EPA, this approach has the advantages of (1) reflecting hazards in the  context of dose, route, duration, and timing of exposure; and (2) avoiding  the potential to label chemicals as toxicants on a purely qualitative basis.
section_title: Dose-Response Assessment
paragraphs: Risk assessors conducting dose-response assessments must make basic  choices regarding which data to base analyses upon and which models and  assumptions to use for extrapolation of study results to the potential  human exposures of regulatory interest.  Data choices focus on the  availability and quality of human or animal studies.  Three of the more  important extrapolation tasks are estimation of low-dose relationships (i.e.,  those that fall below the range of observation in the studies supporting the  agency’s analysis), calculation of toxicologically equivalent doses when  dose-response data from animal studies are applied to human exposures,  and extrapolating results from data on one route of exposure to another  route.
The two main types of studies that provide data useful in a quantitative  dose-response assessment are (1) epidemiological studies of human  populations and (2) toxicological laboratory studies using animals or,  sometimes, human cells.  Epidemiological studies examine the occurrence  of adverse health effects in human populations and attempt to identify the  causes.  At a minimum, such studies can establish a potential link between  exposures to chemical agents and the occurrence of particular adverse  effects by comparing differences in exposed and nonexposed populations.   If there is adequate information on the exposure levels associated with  adverse effects, these studies can also provide the basis for a dose- response assessment.  Because such data obviate the need to extrapolate  from animals to humans, EPA (like other agencies) prefers to use data from  epidemiological studies, if available.
Often, however, the available data for dose-response assessment will come  from animal studies.  A common assumption underlying risk assessments  by EPA (and other agencies) is that an agent that produces adverse effects  in animals will pose a potential hazard to humans.  EPA’s guidelines  emphasize that case-specific judgments are necessary in considering the  relevance of particular studies and their data.  However, in the absence of  definitive information to the contrary, EPA’s guidelines establish some  standard default choices to assist risk assessors in selecting which studies  and data to use.  (See the section on assumptions in this appendix for more  information on such default choices and assumptions.)
Quantifying risks engenders another set of issues and choices.  In  particular, some type of low-dose extrapolation is usually necessary, given  that the doses observed in studies tend to be higher than the levels of  exposure of regulatory concern.  There are limits to the ability of both  epidemiological and toxicological studies to detect changes in the  likelihood of health effects with acceptable statistical precision, especially  at the low-dose exposures typical of most environmental exposures and  given practical limits to the sizes of research studies.
A number of different models might be used for extrapolation, all giving  plausible results.  In its proposed revision of the carcinogen risk  assessment guidelines, EPA identifies use of a biological extrapolation  model as the preferred approach for quantifying risk.  Such models  integrate events in the carcinogenic process throughout the dose-response  range from high to low doses and include physiologically based  pharmacokinetic (PBPK) and biologically based dose-response models.   PBPK models address the exposure-dose relationship in an organism taken  as a whole, estimating the dose to a target tissue or organ by taking into  account rates of absorption into the body, metabolism, distribution among  target organs and tissues, storage, and elimination of an agent.  Biologically  based dose-response models describe specific biological processes at the  cellular and molecular levels that link target-organ dose to the adverse  event.  These models are useful in extrapolation between animals and  humans and between children and adults because they allow consideration  of species- and age-specific data on physiological factors affecting dose  levels and responses.  However, biological models require substantial  quantitative data and adequate understanding of the carcinogenic process  for a specific agent.  EPA cautions that the necessary data for using such  models will not be available for most chemicals.  Therefore, the agency’s  guidelines describe alternative methods.
Dose-response assessment is a two-step process when a biologically based  model is not used.  The first step is the assessment of observed data to  derive a point of departure, and the second step is extrapolation from that  point of departure to lower (unobserved) exposures.  According to EPA  guidelines, the agency’s standard point of departure for animal studies is  the effective dose (ED) corresponding to the lower 95-percent confidence  limit on a dose associated with 10-percent extra risk (LED) compared to  the control group.  EPA may use a lower point of departure for data from  human studies of a large population or from animal studies when such data  are available.  For the extrapolation step, EPA’s proposed guidelines  provide three default approaches which assume, respectively, that the  dose-response relationship is linear, nonlinear, or both.  The choice of  which default approach to apply is to be based on the available information  on the mode(s) of action of the chemical agent. is chosen to account protectively for experimental variability  and is an appropriate representative of the lower end of the observed range, because the  limit of detection in studies of tumor effects is about 10 percent.
section_title: Exposure Assessment
paragraphs: EPA’s program offices usually perform the exposure assessment step, given  the different exposure scenarios of interest for the separate regulatory  programs.  However, EPA has published agencywide guidelines for  exposure assessment that describe general principles and practices for  conducting such assessments.  The focus of EPA’s guidelines is on human  exposures to chemical substances, but the agency noted that much of the  guidance also applies to wildlife exposure to chemicals or human exposure  to biological, physical (e.g., noise), or radiological agents.  EPA points out,  though, that assessments in these other areas must consider additional  factors that are beyond the scope of the exposure assessment guidelines.
EPA’s guidelines establish a broad framework for agency exposure  assessments by describing the general concepts of exposure assessment,  standardizing the terminology (such as defining concepts of exposure,  intake, uptake, and dose), and providing guidance on the planning and  implementation of an exposure assessment.  The guidelines are not,  however, intended to serve as a detailed instructional guide.  EPA’s  guidance prescribes no standard format for presenting exposure  assessment results, but recommends that all exposure assessments, at a  minimum, contain a narrative exposure characterization section that  provides a statement of purpose, scope, level of detail, and approach  used in the assessment, including key assumptions;  presents the estimates of exposure and dose by pathway and route for  individuals, population segments, and populations in a manner  appropriate for the intended risk characterization;  provides an evaluation of the overall quality of the assessment and the  degree of confidence the authors have in the estimates of exposure and  dose and the conclusions drawn;  interprets the data and results; and  communicates the results of the exposure assessment to the risk  assessor, who can then use this information with the results from other  risk assessment elements to develop the overall risk characterization.
The guidelines encourage agency staff to use multiple “descriptors” of both  individual and population risks, rather than a single descriptor or risk  value.  The exposure guidelines also emphasize the use of more realistic  estimates of high-end exposures than had been the case in some previous  practices.  In the past, EPA sometimes relied on exposure estimates  derived from a hypothetical “maximally exposed individual” who might  spend, for example, a 70-year lifetime drinking only groundwater with the  highest concentrations of contaminants detected.  According to the 1997  report of the Presidential/Congressional Commission, this approach was  often based on such unrealistic assumptions that it impaired the scientific  credibility of risk assessments.  Now, however, EPA has adopted the use of  distributions of individual exposures as the preferred practice.  EPA’s  guidance indicates that risk assessments should include both central  estimates of exposure (based on either the mean or median exposure) and  estimates of the exposures that are expected to occur in small, but  definable, high-end segments of the population.  EPA states that a high-end  exposure estimate is to be a plausible estimate of the individual exposure  for those persons at the upper end of an exposure distribution.  The  agency’s intent is to convey an estimate of exposure in the upper range of  the distribution, but to avoid estimates that are beyond the true  distribution.
EPA has identified several new directions in its approach to exposure  assessment.  First is an increased emphasis on total (aggregate) exposure  via all pathways.  EPA policy directs all regulatory programs to consider in  their risk assessments exposures to an agent from all sources, direct and  indirect, and not just from the source that is subject to regulation by the  office doing the analysis.  Another area of growing attention is the  consideration of cumulative risks, when individuals are exposed to many  chemicals at the same time.  The agency is also increasing its use of  probabilistic modeling methods, such as Monte Carlo analysis, to analyze  variability and uncertainty in risk assessments and provide better estimates  of the range of exposure, dose, and risk in individuals in the population.
EPA policy directs regulatory programs to pay special attention to the risks  of children and infants.
EPA has produced some reference documents for exposure assessments,  such as the Exposure Factors Handbook.  This handbook is intended to  provide parameter values for use across the agency and to encourage use  of reasonable exposure estimates by providing appropriate data sources  and suggested methods.   The handbook provides a summary of available  statistical data on various factors used to assess human exposure to toxic  chemicals.  These factors include: drinking water consumption; soil  ingestion; inhalation rates; dermal factors including skin area and soil  adherence factors; consumption/intake of fruits and vegetables, fish,  meats, dairy products, homegrown foods, and breast milk; human activity  patterns, such as time spent performing household tasks; consumer  product use; and residential characteristics.  EPA provides recommended  values for the general population and also for various segments of the  population who may have characteristics different from the general  population (e.g., by age, gender, race, or geographic location). EPA  guidance cautions, though, that these general default values should not be  used in the place of known, valid data that are more relevant to the  assessment being done.  The default values used in EPA risk assessments,  however, sometimes vary slightly from the recommended values appearing  in the handbook.  For example, while the handbook’s mean recommended  value for adult body weight is 71.8 kilograms (kg), the handbook also noted  that a value of 70 kg has been commonly assumed in EPA’s risk  assessments.  Similarly, the recommended value to reflect average life  expectancy of the general population is 75 years, but 70 years also has been  commonly assumed in EPA risk assessments.  Officials from EPA program  offices pointed out that they may use different exposure factors in their  risk assessments because they sometimes develop exposure assessment  methods specific to their programs using different data sources or  population characteristics than those used by ORD for the Exposure  Factors Handbook.
section_title: Ecological Risk Assessment
paragraphs: Ecological risk assessment is different from human health risk assessment  in that it may examine entire populations of species and measure effects on  partial or whole ecosystems.  Often, the focus is on not just a single  ecological entity, but on the potential adverse effects on multiple species  and their interactions (for example, on the food chain).  While human  health risk assessment is primarily concerned with an agent’s toxicity to  humans, ecological risk assessment might consider a range of adverse  effects on natural resources (such as crops, livestock, commercial  fisheries, and forests), wildlife (including plants), aesthetic values,  materials or properties, and recreational opportunities.  For example, a  chemical agent could be considered a risk to wildlife if exposure to it  caused death, disease, behavioral abnormalities, mutations, or deformities  in the members of a species or their offspring.  It could be considered a risk  to aesthetic values if it affected the color, taste, or odor of a water source.
By EPA’s definition, ecological risk assessment is a process that evaluates  the likelihood that adverse ecological effects may occur or are occurring as  a result of exposure to one or more “stressors.”  In other words, ecological  risk assessments may be prospective or retrospective, and, in many cases,  both approaches are included in a single risk assessment.  Chemicals are  only one of the possible ecological stressors that EPA might consider, along  with physical and biological ones.  EPA’s guidance focuses on stressors  and adverse ecological effects generated or influenced by human activity,  which could be addressed by the agency’s risk management decisions.
In comparison to human health risk assessment procedures, the  approaches for ecological risk assessment are more recent and less well  developed.  However, as these methods have changed to incorporate and  better characterize dynamic, interconnected ecological relationships, EPA  has updated its guidance documents on the subject, with input from  multiple interested internal and external parties.  According to EPA, the  solicitation of input from an array of sources is based, in part, on the need  to establish a framework for characterizing risks based on numerous  stressors, interconnected pathways of exposure, and multiple endpoints  (adverse effects).
The most recent version of EPA’s framework appears in Guidelines for  Ecological Risk Assessment, published in 1998.  EPA’s guidelines describe  an iterative three-phase process consisting of problem formulation,  analysis, and risk characterization.  These guidelines incorporate many of  the concepts and approaches called for in human health risk assessments.   However, particularly in the addition of a problem formulation phase, the  ecological risk assessment framework deviates from the standard four-step  process used for human health risk assessments.  EPA pointed out that,  unlike human health assessments where the species of concern and the  endpoints (e.g., cancer) have been predetermined, ecological risk  assessments need a phase that focuses on the selection of ecological  entities and endpoints that will be the subject of the assessment.  Table 4  summarizes the activities and expected outcomes for each of the three  phases of an ecological risk assessment.  Prior to these phases, according  to EPA, a planning stage occurs during which risk assessors, risk managers,  and other interested parties are to have a dialogue and scope the problem.
Among the things considered during problem formulation is the selection  of assessment endpoints, which are “explicit expressions of the actual  environmental value that is to be protected.”  This is unlike human health  assessments, where the species of concern and the endpoints have been  predetermined.  The selection of endpoints at EPA has traditionally been  done internally by program offices, but more recently, affected parties or  communities are assisting in the selection of endpoints with their selection  based on ecological relevance, susceptibility, and relevance to management  goals.  Furthermore, conceptual models are developed during the problem  formulation phase.  Such models contain risk hypotheses in the form of  written descriptions and visual representations, outlining predicted  relationships between ecological entities and the stressors to which they  may be exposed.  According to EPA the hypotheses are in effect  assumptions, being based on theory and logic, empirical data,  mathematical models, probability models, and professional judgment.
Subsequently, during the analysis phase data are selected that will be used  on the basis of their utility for evaluating risk hypotheses.  The major items  considered during this phase are the sources and distribution of stressors  in the environment, the extent of contact and stressor-response  relationships, the evidence for causality, and the relationship between what  was measured and the assessment endpoint(s).  Field studies involving  statistical techniques (i.e., correlation, clustering, or factor analysis),  surveys, the formation of indices, and the use of models are approaches to  evaluating the determined risk hypotheses.  (EPA’s guidance on the risk  characterization phase of an ecological risk assessment is discussed in the  final section of this appendix.)
section_title: Program-Specific Risk Assessment Procedures
paragraphs: EPA’s various program offices generally follow the agencywide risk  assessment procedures and guidelines described above.  The major  exception to this is the Chemical Emergency Preparedness and Prevention  Office, which does not follow the NAS four-step process for its risk  assessment procedures because of its focus on risks associated with  accidental chemical releases.  Overall, there is great diversity in the context  for risk assessment activities across EPA’s program offices.  Each program  has different statutory mandates and risk assessment tasks associated with  its specific regulatory authority, and these contribute to variations in the  way the offices conduct risk assessments.  In particular, there are  differences in the exposure assessment step across, and sometimes within,  EPA’s program offices.  This is not surprising, given that EPA’s regulatory  authorities regarding chemical agents primarily vary according to types and  sources of exposure.  Although there are overlaps in these various  exposures to chemicals, EPA’s program offices generally assess and  regulate different aspects of the risks associated with exposures to humans  and/or the environment.  There are also some variations in the conduct of  hazard identification and dose-response analysis.  The following sections  summarize the risk assessment activities and procedures of those EPA  program offices that are most likely to conduct assessments involving  chemical risks.  The descriptions highlight some of the major variations  and similarities across the program offices.
subsections: section_title: Office of Pesticide Programs
paragraphs: OPP is part of EPA’s Office of Prevention, Pesticides and Toxic Substances  (OPPTS).  The primary risk assessment-related activities of OPP are the  registration of pesticides and the setting of tolerances for pesticide  residues.  Registration involves the licensing of pesticides for sale and use  in agriculture and extermination.  No chemical may be sold in the United  States as a pesticide without such registration, which establishes the  conditions of legal use.  All uses within the scope of the registration  conditions and limits are permissible, although actual practice may vary.   Pesticide tolerances are the concentrations (maximum pesticide residue  levels) permitted to remain in or on food, as it is available to the consumer.   Registrations and tolerances are obtained through petitions to OPP.  The  petitioner has the primary responsibility to provide the data needed to  support registration and tolerances, including information on the  toxicological effects of the pesticide.
There are three major risk statutes affecting EPA’s actions regarding  pesticides. Registration is carried out under the Federal Insecticide,  Fungicide, and Rodenticide Act (FIFRA).  Tolerances are established under  the Federal Food, Drug, and Cosmetic Act (FFDCA).  In 1996, Congress  amended both FIFRA and FFDCA through the FQPA, which mandated  some key changes in risk assessment of pesticides.
Major features and characteristics of chemical risk assessment by OPP are  summarized below.
OPP conducts all steps of risk assessments.  Because OPP generally  follows the NAS four-step process for human health risk assessment and  the EPA-wide risk assessment guidelines, most of its procedures mirror  those used elsewhere in the agency.
OPP officials noted that, over the last three decades, their office has  developed a rigorous process to support the development of chemical  risk assessments.  This process includes regulations to establish  baseline data requirements and published guidelines for conducting  required studies.  OPP officials emphasized the transparency of the  process used to develop EPA’s risk assessment procedures and the  transparency of the procedures EPA uses to make decisions on the risk  of individual pesticides.  As an example, they noted that their program  has consulted with outside experts and asked for public comment on its  guidelines for reviewing studies, science policies for assessing the  significance of study data, and standard operating procedures for  implementing these policies in the development of a hazard  identification or exposure assessment for a chemical.  They also pointed  out that OPP adopted a public participation process for reregistration  and tolerance reassessment decisions on registered pesticides and that  they publish for public comment proposed tolerances for proposed new  uses of pesticides.  In some circumstances, OPP consults with outside  experts concerning a risk assessment of an individual pesticide.
Pesticide registration decisions are based primarily on OPP’s evaluation  of the test data provided by petitioners (applicants).  EPA has  established a number of requirements, such as the Good Laboratory  Practice Standards, to ensure the quality and integrity of pesticide data.   OPPTS has also developed harmonized test guidelines for use in the  testing of pesticides and toxic substances and the development of test  data that must be submitted to EPA for review under federal  regulations.  Depending on the type of pesticide, OPP can require more  than 100 different tests to determine whether a pesticide has the  potential to cause adverse effects to humans, wildlife, fish, and plants.
The FQPA established a single, health-based standard—“reasonable  certainty of no harm”—for pesticide residues in all foods.  All existing  tolerances that were in effect when the FQPA was passed are to be  reevaluated by 2006 to ensure that they meet the new safety standard.   The law requires EPA to place the highest priority for tolerance  reassessment on pesticides that appear to pose the greatest risk.  To  make the finding of “reasonable certainty of no harm” OPP considers: 1. the toxicity of the pesticide and its break-down products; 2. how much of the pesticide is applied and how often; and 3. how much of the pesticide remains in or on food by the time it is  marketed and prepared (the residue).
Among other key changes affecting OPP’s risk assessments when setting  tolerances, the FQPA requires the agency to: 1.  Explicitly address risks to infants and children and to publish a specific  safety finding before a tolerance can be established.  It also requires an  additional tenfold uncertainty factor (unless reliable data show that a  different factor will be safe) to account for the possibly greater  sensitivity and exposure of children to pesticides. 2.  Consider aggregate exposure from a pesticide, including all anticipated  dietary and all other exposures for which there is reliable information.   These include exposures through food, drinking water, and nondietary  exposures encountered through sources in the home, recreational  areas, and schools.  3.  Consider cumulative exposures to pesticides with a common  mechanism of toxicity, which previously had been considered  separately.
Title III of the FQPA also requires certain data collection activities of the  Secretary of Agriculture, in consultation or cooperation with the  Administrator of EPA and the Secretary of Health and Human Services,  regarding food consumption patterns, pesticide residue levels, and  pesticide use that, according to EPA, affect its risk assessments when  setting tolerances.
Also as a result of the FQPA, OPP uses a population adjusted dose  (PAD), which involves dividing the acute or chronic reference dose by  the FQPA uncertainty factor.  According to OPP officials, this allowed  OPP to be consistent with the rest of the agency regarding setting RfDs,  but still use the FQPA factor for regulating pesticides.
OPP is concerned with both cancer and noncancer toxicity.  However,  for noncancer effects, OPP has paid special attention to neurotoxicity  (because many pesticides work through this mechanism) and, more  recently, to endocrine disrupting effects (those affecting the body’s  hormone system).
OPP officials noted that, while their agency has made important use of  “real life” monitoring or incident data, it primarily relies on studies  conducted in laboratory animals and on laboratory or limited field  studies.  They stated that, in their experience, “real life” data have  profound limitations and that such data are inconsistent, expensive,  inconclusive, and are not available for premarket decision making.   They said that, most importantly, by the time there are observable health  or environmental effects, it is too late to prevent the harm that could  have been predicted from judicious use of animal or environmental fate  studies conducted in the laboratory.
During the exposure assessment step, OPP is concerned with a variety  of routes, sources, and types of exposure.  The three routes by which  people can be exposed to pesticides are inhalation, dermal (absorbing  pesticides through the skin), and oral (getting pesticides in the mouth or  digestive tract).  Depending on the situation, a pesticide could enter the  body by any one or all of these routes.  Typical sources of pesticide  exposure include food, home and personal use of pesticides, drinking  water, and work-related exposure to pesticides (in particular, to  pesticide applicators or vegetable and fruit pickers).  In its approach to  exposure assessment, OPP distinguishes between residential and  occupational types of exposures.   OPP officials noted that their  program is further developing procedures to conduct drinking water  exposure assessments and residential exposure assessments and that  they have new procedures for ecological risk assessments.
OPP calculates estimates of acute (i.e., short-term) pesticide exposure  slightly differently from those for chronic (i.e., longer-term) exposures.   This is because an acute assessment estimates how much of a pesticide  residue might be consumed in a single day, while a chronic assessment  estimates how much might be consumed on a daily basis over the  course of a lifetime.  In an important difference, acute assessments are  based on high-end individual exposure assumptions, while chronic  assessments use average exposure assumptions.
In assessing both acute and chronic risks, OPP uses a tiered approach,  starting with an initial screening tier and proceeding through  progressively more elaborate risk assessments, if needed.  The  analytical tiers proceed from more conservative to less conservative  assumptions.  For the first-tier risk assessment, OPP uses “worst-case”  assumptions (e.g., that pesticide residues are at tolerance levels and that  100 percent of the food crop is treated with the pesticide) that give only  an upper-bound estimate of exposure.  For more refined analyses, OPP  officials noted that they have new procedures for conducting  probabilistic dietary exposure assessments.  Generally, the level of  resources and the data needed to refine exposure estimates increase  with each tier.  Typically, if risks from pesticide residues are not of  concern using lower-tier exposure estimates, OPP does not make  further refinements through additional tiers.  However, with the  aggregate and cumulative exposure assessments now required by the  FQPA, EPA notes that it is likely that higher-tier exposure estimates will  be needed.
The agency has developed procedures for modeling the environmental  fate of pesticides.  OPP officials said that these models use real data on  the physical and chemical properties of the pesticide, information on the  proposed or actual uses of the pesticide, and real data on the movement  of pesticides or other materials through soil, air, water, skin, textiles, or  other media to predict potential exposures to a pesticide.  These models  are guided by scientific judgments that are based upon data and  scientists’ experience in drawing inferences from these data.
section_title: Office of Pollution Prevention and Toxics
paragraphs: OPPT (formerly the Office of Toxic Substances) is also part of OPPTS.   OPPT was established to implement the Toxic Substances Control Act  (TSCA), which authorizes EPA to screen existing and new chemicals used  in manufacturing and commerce to identify potentially dangerous products  or uses.  TSCA focuses on the properties of a chemical and paths of  exposure to that chemical.  Risk assessment activities are primarily related  to four sections of TSCA:  Section 4 directs EPA to require manufacturers and processors to  conduct tests for existing chemicals when: (1) their manufacture,  distribution, processing, use, or disposal may present an unreasonable  risk of injury to health or the environment; or (2) they are to be  produced in substantial quantities and the potential for environmental  release or human exposure is substantial or significant.  Under either  condition, EPA must issue a rule requiring testing if existing data are  insufficient to predict the effects of human exposure and environmental  releases and testing is necessary to develop such data.  Rhomberg  pointed out that these conditions require OPPT to do some preliminary  risk assessment and that, unlike testing mandates under other statutes  (e.g., regarding pesticides), the agency has the burden of showing that  such testing is necessary.
Section 5 addresses future risks through EPA’s premanufacture  screening—the premanufacture notification (PMN) process.  This also  applies to a “significant new use” of an existing chemical.
Section 6 directs EPA to control unreasonable risks presented or that  will be presented by existing chemicals.
Section 8 requires EPA to gather and disseminate information about  chemical production, use, and possible adverse effects to human health  and the environment.  This section requires EPA to develop and  maintain an inventory of all chemicals, or categories of chemicals,  manufactured or processed in the United States.  All chemicals not on  the inventory are, by definition, “new” and subject to the notification  provisions of section 5.  Once a chemical enters commerce through the  section 5 process, it is listed as an existing chemical.
Although TSCA gives EPA general authority to seek out and regulate any  “unreasonable risk” associated with new or existing chemicals, there are  two major limitations on the agency’s regulatory actions.  First, as  implemented by EPA, regulation under TSCA involves consideration of  both risks and applying the least burdensome requirement needed to  regulate the risk.  The term “unreasonable risk” is not defined in TSCA.   However, according to EPA, the legislative history indicates that  unreasonable risk involves the balancing of the probability that harm will  occur, and the magnitude and severity of that harm, against the effect of a  proposed regulatory action on the availability to society of the expected  benefits of the chemical substance.  The second major limitation on EPA’s  authority under TSCA is a requirement to defer to other federal laws.   Generally, if a risk of injury to health or the environment could be  eliminated or reduced to a sufficient extent by actions taken under another  federal law, that other law must be deferred to unless it can be shown to be  in the public interest to regulate under TSCA.
The major distinction in the procedures that apply to OPPT risk  assessments is between the evaluation of potential risks associated with  exposures to new versus existing chemicals.  For EPA to control the use of  a chemical listed on the inventory of existing chemicals, according to  OPPT, a legal finding has to be made that the chemical will present an  unreasonable risk to human health or the environment.  According to  OPPT, this standard requires the agency to have conclusive data on that  particular chemical.  The agency noted, in comparison, that newly  introduced chemicals (or uses) can be regulated under TSCA based on  whether they may present an unreasonable risk, and this finding of risk can  be based on data for structurally similar chemicals.  Because industrial  chemicals in commerce in 1975-1977 were “grandfathered” into the  inventory without considering whether they were hazardous, there are  situations in which existing chemicals might not be controlled, while EPA  would act to control a new chemical of similar or less toxicity under the  PMN program.  Additional information on the major features and  characteristics of assessments for new versus existing chemicals is  presented below.
Premanufacture notification for new chemicals or significant new uses  TSCA requires manufacturers, importers, and processors to notify EPA  at least 90 days prior to introducing a new chemical into the U.S. or  undertaking a significant new use of a chemical already listed on the  TSCA inventory.  If available, test data and information on the  chemical’s potential adverse effects on human health or the  environment are to be submitted to EPA.  Much of this submission must  be kept confidential by OPPT.  However, there is no defined toxicity data  set required before PMN, and, unless EPA promulgates a rule requiring  the submission of test data, TSCA does not require prior testing of new  chemicals.  Consequently, according to EPA, less than half of the PMNs  submitted include toxicological data.  OPPT reviews approximately  1,500 PMNs annually.
EPA has 90 days after notification to evaluate the potential risk posed by  the chemical.  EPA must then decide whether to (1) permit manufacture  and distribution (the default if EPA takes no action), (2) suspend  manufacture and distribution or to restrict use pending the development  of further data, or (3) initiate rulemaking to regulate manufacture or  distribution.
OPPT typically has very limited chemical-specific data on toxic effects  and exposure associated with new chemicals.  When no data exist on  the effects of exposure to a chemical, EPA may make its determination  on what is known about the chemical’s molecular structure (called the  structure-activity relationship, or SAR) and the effects of other  chemicals that have similar structures and are used in similar ways.   OPPT’s New Chemicals Program has issued a document entitled  Chemical Categories that describes information for numerous classes  of chemicals.  In assessing exposures for new chemicals where  exposure monitoring data are unavailable, OPPT uses several screening- level approaches, including (1) estimates based on data on analogous  chemicals; (2) generic scenarios (i.e., standardized approaches for  assessing exposure and release for a given use scenario); (3)  mathematical models based on empirical and theoretical data and  information; and (4) assumptions of compliance with regulatory limits,  such as OSHA Permissible Exposure Limits (PELs).
Rhomberg noted that OPPT cannot require full testing for all chemicals,  because of statutory limitations under TSCA.  He therefore  characterized OPPT’s assessments as “rough screens” designed to flag  situations in which further testing should be required.
Chemicals that OPPT assesses for regulation under sections 4 or 6 of  TSCA are subject to a more rigorous risk assessment process.   Compared to PMN reviews, such assessments are much more similar to  those conducted elsewhere in EPA, so the EPA-wide guidelines  generally apply.
For hazard identification and dose-response assessment of carcinogens  and noncancer effects, OPPT follows EPA-wide procedures.  Because  TSCA focuses on the properties of a chemical, rather than on a specific  pathway or mode of exposure, OPPT considers the potential hazards  posed through multiple routes of exposure.  In lieu of information to the  contrary, OPPT typically presumes that the results for one route are  applicable to other routes.
Similarly, in exposure assessment OPPT considers a variety of types and  routes of exposure.  Unlike other programs that focus on exposure  through one medium, assessments under TSCA must assess all potential  exposures to a chemical that may lead to unreasonable risk,  considering, for example, both residential and occupational exposures.   These risks may be assessed separately for each mode of exposure, even  if occurring in the same setting.  Overall, OPPT aims to provide both  central estimates and upper-bound estimates of exposure, and it  considers population risks as well as individual risks.
OPPT shares overlapping concerns about a number of different kinds of  exposure with other federal regulatory agencies.  However, some  aspects of OPPT’s exposure assessments may differ from those of other  programs or agencies concerned with similar exposures.  For example,  with regard to occupational exposures OPPT assumes that a working  lifetime is 40 years, rather than the 45 years assumed by OSHA.  Another  example is the assumption of body weight; OPPT uses 70kg, whereas  ORD recommends a value of 71.8 kg in its Exposure Factors Handbook.
In addition to the assessment of chemicals for regulation under sections 4  and 6 of TSCA, OPPT has recently launched a new program to voluntarily  add screening-level hazard information on approximately 2,800 high- production-volume industrial chemicals and has proposed a second new  voluntary program to address the risks of certain industrial chemicals to  which children may be exposed.  These two new programs operate under  the same risk assessment processes used in the other OPPT programs  noted above.
section_title: Office of Emergency and Remedial Response (Superfund Program)
paragraphs: OERR is part of EPA’s Office of Solid Waste and Emergency Response  (OSWER).  Risk assessments are a required component of a larger  remediation process established by the Comprehensive Environmental  Response, Compensation, and Liability Act of 1980 (CERCLA or  Superfund), as amended by the Superfund Amendments and  Reauthorization Act of 1986 (SARA).  Congress enacted CERCLA to  facilitate the cleanup of hazardous waste sites.  The act gave EPA broad  authority to respond to releases of hazardous substances.  SARA requires  EPA to emphasize cleanup remedies that treat—rather than simply  contain—contaminated waste to the maximum extent practicable and to  use innovative waste treatment technologies.
Hazardous substances are defined by CERCLA to include substances  identified under the Solid Waste Disposal Act, the Clean Water Act, the  Clean Air Act, and the Toxic Substances Control Act, or designated by EPA.   After investigating potentially hazardous sites, EPA ranks them according  to the severity of their waste problems and places the worst on its National  Priorities List for Superfund cleanup.  Under CERCLA section 105, EPA  uses a Hazard Ranking System to decide which sites to include on the list.   Section 105 states that priorities are to be based upon relative risk or  danger to public health or welfare or the environment, taking into account  the population at risk, the hazard potential of the hazardous substances,  and the potential for contamination of air and drinking water, among other  factors.
OERR has developed a human health and environmental evaluation  process as part of its remedial response program.  Major features and  characteristics of the Superfund risk assessment procedures are  summarized below.
Overall, the risk scenarios for Superfund can be very complex.
Superfund sites are often associated with multiple potential pathways  and routes of exposure, and mixtures of chemicals at Superfund sites  are common.  In addition, the Superfund program is required to consider  ecological as well as human health risks.
A risk assessment is performed after a particular site has been identified  according to the National Contingency Plan, EPA’s regulation outlining  requirements relevant to response action(s) for hazardous substances.   The remedial response process under the National Contingency Plan— and the role of risk information in the process—is summarized in the  following seven steps: 1. Site discovery or notification:  report determinations about which substances are hazardous. 2. Preliminary assessment and site inspection:  collect and review all available information to evaluate the  source and nature of hazardous substances.
3. Hazard ranking system:  compile data from steps one and two in a numerical scoring  model to determine a relative risk measure. 4. Possible inclusion of site on the National Priorities List based on one  of the following criteria:  the release scores sufficiently high pursuant to the Hazard   a state designates a release as its highest priority, or  the release satisfies all of the following criteria:  the Agency for Toxic Substances and Disease Registry has issued  a health advisory that recommends dissociation of individuals  from the release, EPA determines that the release poses a significant threat to  public health, and  EPA anticipates that it will be more cost effective to use its  remedial authority than to use removal authority to respond to  the release. 5. Remedial investigation and feasibility study:  characterize the contamination at site where data is obtained to  identify, evaluate, and select cleanup alternatives.
6. Selection of a remedy:  choose remedy that is protective of human health and the  environment by eliminating, reducing, or controlling risks posed  through each pathway, and  utilize risk information obtained during step five.
7. 5-year review.
One intended result of the remedial steps is the facilitation of a site- specific baseline risk assessment, designed to support risk management  decision making.  Human health and ecological risk assessments occur  during step five, the Remedial Investigation/Feasibility Study stage.
For human health risk assessments, Superfund procedures approximate  the NAS paradigm, using the following four stages. 1. A data collection and evaluation stage that involves:  gathering and analyzing site data relevant to the human health   identifying substances present at the site that are the focus of the risk  assessment process. 2. An exposure assessment that involves:  analyzing contaminant releases,  identifying exposed populations,  identifying potential exposure pathways and estimating exposure  concentrations for pathways, and  estimating contaminant intakes for pathways. 3. A toxicity assessment stage that considers:  types of adverse health effects associated with chemical exposures,  relationships between magnitude of exposure and adverse effects,  related uncertainties such as the weight evidence of a particular  chemical’s carcinogenicity in humans, and  existing toxicity information developed through hazard identification  and dose-response assessment. 4. A risk characterization that involves:  characterizing potential for adverse health effects (cancer or  noncancer) to occur,  evaluating uncertainty, and  summarizing risk information.
For ecological risk assessments, EPA’s guidelines suggest that  Superfund remedial actions generally should not be designed to protect  organisms on an individual basis, but should protect local populations  and communities of biota.  Furthermore, except for a few very large  sites, Superfund ecological risk assessments typically do not address  effects on entire ecosystems.  Instead, they gather data regarding the  effects on individuals in order to predict or postulate potential effects  on local wildlife, fish, invertebrate, and plant populations and  communities that occur or that could occur in specific habitats at sites  (e.g., a wetland, floodplain, stream, estuary, or grassland).  Specifically,  the guidelines recommend that ecological risk assessments performed  at every site follow an eight-step process: 1. Screening-level problem formulation and ecological effects evaluation:  site history,  site visit,  problem formulation, and  ecological effects evaluation. 2. Screening-level exposure estimate and risk calculation:  exposure estimate, and  risk calculation. 3. Baseline risk assessment problem formation:  ecotoxicity literature review,  exposure pathways,  assessment endpoints and conceptual model, and  risk questions. 4. Measurement endpoints and study design. 5. Verification of field sampling design. 6. Site investigation and data analysis. 7. Risk characterization. 8. Risk management.  OERR uses a tiered approach for Superfund risk assessments, in which  the agency employs more conservative methods and assumptions in the  initial screening phases, followed by a more rigorous, multistage risk  assessment if screening results indicate the need.  Under Superfund,  decisions generally are made on a site-by-site basis.  According to  agency officials, early activities at Superfund sites are often based on  initial tier screening.  However, they pointed out that the remedial  cleanup decision is supported by a site-specific risk assessment that is  usually quite detailed with either site-specific exposure assumptions or  national default assumptions appropriate to the site which result in  “high-end” reasonable risk estimates.  Although the Superfund program  initially employed an approach of using a hypothetical “worst case”  scenario for exposure assessments, EPA’s exposure assessment  guidance now emphasizes use of a more realistic upper-bound exposure  scenario.  The EPA guidelines emphasize that this exposure scenario  should be in the range of plausible real exposures, and also call for a  central tendency case.  In addition, guidelines put forth by the  Superfund program office emphasize streamlining the process and  reducing the cost and time required, focusing on providing information  necessary to justify action and select the best remedy for a Superfund  site.  In doing so, Superfund guidelines suggest using standardized  assumptions, equations, and values wherever appropriate.
The Superfund program uses extensive additional program-specific  guidance documents addressing human health and ecological risk  assessments, as well as analytical tools, such as probabilistic analysis.   These documents supplement applicable EPA-wide guidelines.  The  Superfund guidelines for human health risk assessment, for example,  cover developing a baseline risk assessment (Part A), developing or  refining preliminary remediation goals (Part B), performing a risk  evaluation of remedial alternatives (Part C), and standardizing,  planning, reporting, and completing a review (Part D).  There are also  other headquarters and regional office documents that further  supplement the program-specific guidelines and manuals.
section_title: Office of Solid Waste
paragraphs: The Office of Solid Waste, like OERR, is part of OSWER.  OSW regulates the  management of solid waste and hazardous waste through federal programs  established by the Resource Conservation and Recovery Act of 1976, as  amended (RCRA).  Congress enacted RCRA to protect human health and  the environment from the potential hazards of waste disposal, conserve  energy and natural resources, reduce the amount of waste generated, and  ensure that wastes are managed in a manner that is protective of human  health and the environment.  The act defines solid and hazardous waste,  authorizes EPA to set standards for facilities that generate or manage  hazardous waste, and establishes a permit program for hazardous waste  treatment, storage, and disposal facilities.  The RCRA hazardous waste  program has a “cradle to grave” focus, regulating facilities that generate,  transport, treat, store, or dispose of hazardous waste from the moment it is  generated until its ultimate disposal or destruction.
RCRA regulations interact closely with other environmental statutes,  especially CERCLA.  EPA notes that both programs are similar in that they  are designed to protect human health and the environment from the  dangers of hazardous waste, but each has a different regulatory focus.   RCRA mainly regulates how wastes should be managed to avoid potential  threats to human health and the environment.  On the other hand,  according to EPA, CERCLA is relevant primarily when mismanagement  occurs or has occurred, such as when there has been a release or a  substantial threat of a release in the environment of a hazardous substance.
Regulatory activity under RCRA focuses primarily on specifying  procedures and technology to be used to ensure proper handling and  disposal of wastes, but risk assessments play a role in several supporting  tasks, particularly those involving hazardous waste regulation under RCRA  Subtitle C.  For example, risk assessment information may be used in the  processes for defining (and delisting) substances as hazardous wastes,  evaluating the hazards posed by waste streams, assessing the need for  corrective action at disposal sites, and granting waste disposal permits  (such as incinerator permits).  In its RCRA Orientation Manual, OSW  expressed an increasing emphasis on making the RCRA hazardous waste  program more risk based (with the intention of ensuring that the  regulations correspond to the level of risk posed by the hazardous waste  being regulated).  Major features and characteristics of risk assessment for  hazardous waste regulation are summarized below.
Making the determination of whether a substance is a hazardous waste  is a central component of the waste management program.  The Subtitle  C program includes procedures to facilitate this identification and  classification of hazardous waste.  Under the RCRA framework,  hazardous wastes are a subset of solid wastes.  In RCRA §1004(5),  Congress defined hazardous waste as a solid waste, or combination of  solid wastes, which because of its quantity, concentration, or physical,  chemical, or infectious characteristics may:  cause, or significantly contribute to, an increase in mortality or an  increase in serious irreversible, or incapacitating reversible, illness;  or  pose a substantial present or potential hazard to human health or the  environment when improperly treated, stored, transported, or  disposed of, or otherwise managed.
EPA developed more specific criteria for defining hazardous waste using  two different mechanisms:  (1) listing certain specific solid wastes as  hazardous and (2) identifying characteristics (physical or chemical  properties) which, when exhibited by a solid waste, make it hazardous.   The agency has done so, and risk assessment information may be used to  support both mechanisms. “Listed wastes” are wastes from generic industrial processes, wastes  from certain sectors of industry, and unused pure chemical products  and formulations.  EPA uses four criteria to decide whether or not to list  a waste as hazardous. 1. The waste typically contains harmful chemicals (and exhibits other  factors, such as risk and bioaccumulation potential) which indicate that  it could pose a threat to human health and the environment in the  absence of special regulation.  Such wastes are known as toxic listed  wastes. 2. The waste contains such dangerous chemicals that it could pose a  threat to health or the environment even when properly managed.   These wastes are fatal to humans and animals even in small doses and  are known as acute hazardous wastes. 3. The waste typically exhibits one of the four characteristics of  hazardous waste: ignitability, corrosivity, reactivity, and toxicity. 4. EPA has cause to believe that, for some other reason, the waste  typically fits within the statutory definition of hazardous waste.
Listed hazardous wastes can exit Subtitle C regulation through a site- specific delisting process initiated by a petition from a waste handler to an  EPA region or a state.  The petition must demonstrate that, even though a  particular waste stream generated at a facility is a listed hazardous waste, it  does not pose sufficient hazard to merit RCRA regulation.  “Characteristic wastes” are wastes that exhibit measurable properties  that indicate they pose enough of a threat to deserve regulation as  hazardous wastes.  EPA established four hazardous waste  characteristics.
1.
Ignitability identifies wastes that can readily catch fire and sustain  combustion. 2. Corrosivity identifies wastes that are acidic or alkaline.  Such wastes  can readily corrode or dissolve flesh, metal, or other materials. 3. Reactivity identifies wastes that readily explode or undergo violent  reactions (e.g., when exposed to water or under normal handling  conditions). 4. Toxicity is used in a rather narrow and specific sense under this  program to identify wastes that are likely to leach dangerous  concentrations of chemicals into ground water if not properly managed  (and thus expose users of the water to hazardous chemicals and  constituents).
EPA developed a specific lab procedure, known as the Toxicity  Characteristic Leaching Procedure, to predict whether any particular waste  is likely to leach chemicals into ground water at dangerous levels.  In this  procedure, liquid leachate created from hazardous waste samples is  analyzed to determine whether it contains any of 40 different common  toxic chemicals in amounts above specified regulatory levels.  The  regulatory levels are based on ground water modeling studies and toxicity  data that calculate the limit above which these toxic compounds and  elements will threaten human health and the environment.
For OSW, the task of identifying and assessing hazardous wastes is  made more difficult because waste may be in the form of a mixture of  constituents, some of which may be hazardous and some not.  (This is  also a common issue for the Superfund program.)  The EPA-wide  guidelines on assessments of chemical mixtures therefore could come  into play in OSW risk assessments.
For dose-response data on the toxicity and potency of hazardous  substances, OSW largely relies on information from other EPA sources.   For example, OSW may use the chemical-specific assessments prepared  by ORD, data in EPA’s IRIS database, and regulatory standards from  other EPA program offices, in particular the Office of Water.  However,  OSW combines this information with its own exposure analyses.
Rhomberg categorized exposure assessment by OSW as either  hypothetical or site specific.  He noted that hypothetical exposures  principally come into play when the agency is defining hazardous  wastes and evaluating disposal options.  These exposure analyses cover  hypothetical waste-handling and disposal practices anywhere in the  nation, and OSW focuses on the question of whether such practices  might cause undue risks to individuals, not on characterizing the actual  distribution of exposures across the population.  One of the principal  concerns in OSW exposure assessments is leaching to groundwater, but  OSW evaluates other exposure pathways from virtually all treatment  and disposal practices, with the specific pathways for any particular  analysis being decided on a case-by-case basis.  Site-specific exposure  assessments might be needed when OSW is making regulatory decisions  regarding actual waste disposal facilities, as when assessing the need for  remedial action at a given site or permitting incineration or other  disposal activities.  In such cases, the office can focus exposure  estimates on the off-site migration of the particular toxic compounds  associated with that location.  In general, an important part of OSW’s  exposure assessments is evaluating the “relative contribution” of  hazardous wastes to the overall exposure to a hazardous chemical  (which is very similar to assessments by EPA’s Office of Water).
In exposure assessments, OSW’s deterministic analyses follow EPA’s  risk characterization guidance by setting only two sensitive parameters  at high-end values, with the rest of the parameters being set at their  central tendency values.  According to OSW, this approach is meant to  produce a risk estimate above the 90th percentile of the risk distribution  but still on the actual distribution.
section_title: Chemical Emergency Preparedness and Prevention Office
paragraphs: CEPPO is also part of OSWER.  It provides leadership, advocacy, and  assistance to: (1) prevent and prepare for chemical emergencies; (2)  respond to environmental crises; and (3) inform the public about chemical  hazards in their community.  To protect human health and the environment,  CEPPO develops, implements, and coordinates regulatory and  nonregulatory programs.  It carries out this work in partnership with EPA  regions, domestic and international organizations in the public and private  sectors, and the general public.
CEPPO is responsible for the risks associated with accidental chemical  releases.  Under the Emergency Planning and Community Right-to-Know  Act (EPCRA) in Title III of the Superfund Amendments and  Reauthorization Act of 1986, CEPPO must evaluate, develop, and maintain  a list of chemicals and threshold quantities that are subject to reporting for  emergency planning.  In addition, CEPPO develops the emergency  reporting and planning requirements, guidance for industry, and guidance  and tools for use of the reporting information by Local Emergency Planning  Committees.  These reporting and planning requirements serve to provide  the necessary information to be used at the local level to manage the risks  associated with accidental chemical releases.
CEPPO is also responsible for accidental chemical release prevention.   Under Section 112(r) of the Clean Air Act, as amended by the Clean Air Act  Amendments of 1990, CEPPO must evaluate chemicals for acute adverse  health effects, likelihood of accidental release, and magnitude of exposure  to develop a list of at least 100 substances that pose the greatest risk of  causing death, injury, or serious adverse effects to human health or the  environment from accidental releases.  Each listed substance must have a  threshold quantity that takes into account the chemical’s toxicity,  reactivity, volatility, dispersability, combustibility, or flammability.
Facilities handling a listed substance above its threshold quantity must  implement a risk management program and develop a risk management  plan.  The risk management program must address a hazards analysis,  prevention program, and emergency response program.  According to  CEPPO officials, they scaled these regulatory requirements according to  the risk posed by the wide range of facilities subject to the requirements— the greater the risk, the greater the risk management responsibilities.  The  facilities submit their risk management plans to EPA and to state and local  officials for use in emergency planning and local risk management and  reduction.  CEPPO investigates chemical accidents, conducts research, and  collects information about chemical and industrial process hazards to issue  Chemical Safety Alerts and other publications to raise awareness about  chemical accident risks.  CEPPO also develops tools, methods, and  guidance necessary to identify and assess the risks to human health from  accidental releases.
Major features and characteristics of CEPPO’s risk assessment procedures  are summarized below.
The chemical risk assessments conducted by CEPPO are unique from  the risk assessments conducted by other EPA offices.  CEPPO’s  procedures do not follow the NAS four-step risk assessment approach,  but are similar to the chemical risk assessment approach used by the  Department of Transportation’s (DOT) Research and Special Programs  Administration (RSPA) in that hazards are identified and a measure of  exposure (or consequence) is determined to yield a “threat” associated  with an accidental release.  While RSPA focuses on risks associated with  accidents involving unintentional releases of hazardous materials during  transportation, CEPPO focuses on risk associated with accidental  releases from a fixed facility.  According to CEPPO, for accidental  release risks, because these events are high consequence and  low  probability, the hazard and exposure typically can be estimated with  some degree of confidence.  However, the likelihood or probability of an  accidental release is very uncertain.  Consequently, likelihood is  addressed only in a limited way and the “threat” is judged to be a  surrogate for risk.
CEPPO’s approaches with respect to chemical accident risk are  published mainly in two rulemakings—“List of Regulated Substances  and Thresholds for Accidental Release Prevention and Risk  Management Programs for Chemical Accident Release Prevention,” 59  FR 4478 (Jan. 31, 1994) and “Accidental Release Prevention  Requirements: Risk Management Programs under the Clean Air Act,  Section 112(r)(7),” 61 FR 31668 (June 20, 1996)—and in guidelines,  especially “Technical Guidance for Hazards Analysis, Emergency  Planning for Extremely Hazardous Substances,” which was issued  jointly by EPA, DOT, and the Federal Emergency Management Agency  (Dec. 1987).
For hazard identification, CEPPO identifies the hazards that pose a risk  to human health and the environment from an analysis of chemical  accidents and of the physical/chemical properties of substances that  make them more likely to cause harm as a result of an accidental  chemical release.  For example, the catastrophic chemical release in  Bhopal, India, in December 1984 involved methyl isocyanate, a chemical  that is toxic when inhaled.  CEPPO identified the criteria necessary to  identify those substances that are so toxic that, upon exposure (i.e.,  inhalation, dermal contact, or ingestion) to a small amount, they cause  death or serious irreversible health effects in a short time (acute  toxicity).  CEPPO also has developed criteria to identify other  substances, such as highly flammable substances that can trigger a  vapor cloud explosion harming the public and environment.  CEPPO is  also working to understand the long-term (chronic) effects that might be  generated by a single acute exposure.
As part of its identification of hazards, CEPPO also evaluates the  quantity of a chemical that would need to be released and travel off-site  to establish a threshold quantity.  If a facility handles more than this  quantity, there is a presumption of risk triggering some action by the  facility’s owner(s) and operator(s).  The hazardous chemicals and  threshold quantities identified by CEPPO are published in rulemakings.
According to CEPPO, the exposure assessment (or consequence  analysis) phase of a chemical accident release assessment is somewhat  unique from the classical risk assessment approaches and procedures.   The actual exposure to humans after an accidental release is often not  known.  In addition, the amount and rate of chemical released and the  precise conditions (e.g., weather) are usually not known.  However,  these parameters can be estimated using engineering calculations and  mathematical models to generate the concentration likely to have been  present or that could be present in a certain type of accidental release.   Using these techniques, chemicals that possess the physical/chemical  properties most likely to harm the public or the environment can be  evaluated to estimate the degree of “threat” that they may pose in an  accidental release.
CEPPO uses these exposure assessment (consequence analysis)  techniques to understand the potential magnitude of exposure  associated with a variety of hazardous chemicals.  In addition, CEPPO  publishes the techniques in guidelines and as software to assist facilities  in their assessment of accidental release risk.  According to CEPPO,  industry has a fundamental responsibility to understand the risks  associated with chemical accidents.  In addition, the Risk Management  Plan requirements under section 112(r) of the Clean Air Act require that  this information be made available to the public so that industry and the  community can work together to manage the risks that might be  present.
CEPPO may characterize the risks associated with accidental releases  using a number of parameters, such as the presence of a large quantity  of a highly hazardous substance in proximity to a large facility that has  had a number of accidental releases in the past.  CEPPO uses these  parameters to place more responsibility on such facilities (e.g., greater  accidental release prevention measures under the Risk Management  Program requirements), to investigate the underlying reasons for their  accidental releases, or to assist in audits and inspections of their  accident prevention programs.
section_title: Office of Air and Radiation
paragraphs: OAR oversees the air and radiation protection activities of the agency.   Radiation risk assessments conducted by OAR are outside the scope of this  report, but chemical risk assessments do have a part in OAR’s efforts to  preserve and improve air quality in the United States.  Such air quality  concerns are the primary mission of OAR’s Office of Air Quality Planning  and Standards (OAQPS), which, among other activities, compiles and  reviews air pollution data and develops regulations to limit and reduce air  pollution.  The Risk and Exposure Assessment and the Health and  Ecosystem Effects Groups within OAQPS provide the scientific and  analytical expertise to conduct and support human health and ecological  risk assessments in this area, in coordination with ORD.
The Clean Air Act, as amended, provides the statutory basis for air-related  risk assessments by OAR.  The CAA requires EPA to establish national  standards for air quality, but it gives states the primary responsibility for  assuring compliance with the standards.  Chemical risk assessments are  primarily associated with regulation of (1) criteria air pollutants and (2)  hazardous air pollutants, also referred to as “air toxics.”
The CAA requires EPA to set health-based air quality standards (National  Ambient Air Quality Standards, or NAAQS) for criteria pollutants, which  are common throughout the United States and mostly the products of  combustion.  Under the CAA, EPA is also required to review the scientific  data upon which the standards are based and revise the standards, if  necessary, every 5 years.  The criteria pollutants are particulate matter,  carbon monoxide, sulfur oxides, nitrogen dioxide, ozone, and lead.  Of  these pollutants, ozone is not directly emitted by a source, but rather is the  product of the interaction of nitrogen oxide, volatile organic compounds,  and sunlight.  Therefore, regulations targeting ozone focus on controlling  emissions of nitrogen oxide and volatile organic compounds.  The CAA  requires EPA to set health-based standards with an “adequate margin of  safety,” but according to EPA it is not required to set air quality standards at  a zero-risk level to achieve an adequate margin of safety, but simply at a  level that avoids unacceptable risks.  EPA therefore sets the standards to  protect the substantial part of the national population, including sensitive  or at-risk populations, but not necessarily the most sensitive or exposed  individuals.
The CAA also contains provisions, first added in 1970, for the regulation of  emissions to the atmosphere of hazardous air pollutants—toxic chemicals  other than the six criteria pollutants.  The 1970 amendments to the CAA  required EPA to identify and control hazardous air pollutants so as to  achieve “an ample margin of safety.”  However, Congress passed another  major set of amendments, the Clean Air Act Amendments of 1990 (CAAA),  which revised the hazardous air pollutant provisions and substantially  affected the application of risk assessment regarding air toxics.  The  amendments explicitly wrote into the act a list of 189 hazardous air  pollutants to be regulated.  In addition, the amendments replaced the  former health-based criterion for standards with a criterion that is  primarily technology based, mandating the maximum achievable control  technology (MACT) for the specified list of chemicals.  The act further  mandates that EPA evaluate residual risks remaining after implementation  of the MACT standards to determine if additional standards are needed to  protect the public health with an ample margin of safety.
Additional information on the major features and characteristics of  chemical risk assessments related to these air quality protection activities  is presented below.
There are several unique features that affect risk assessments for  criteria air pollutants.  Compared to many other agents assessed by  EPA, the agency generally has extensive human data available on health  effects at relevant exposure levels.  Therefore, risk assessments for  criteria air pollutants require little extrapolation across species or to  low doses and few default assumptions.  These are the least likely of  EPA’s risk assessments to use precautionary or conservative methods  and assumptions, and the results are intended to be unbiased estimates  without any built-in conservatism.
For criteria air pollutants, “hazard identification” information on health  effects appears primarily in air quality criteria documents prepared by  ORD and staff papers prepared by OAQPS to support the review and  development of national ambient air quality standards.  These  documents are intended to reflect the available scientific evidence on  toxicity endpoints of concern.  The definition of what responses  constitute “adverse” outcomes is ultimately left to the Administrator’s  judgment, informed by staff recommendations, advice from the Clean  Air Scientific Advisory Committee (part of EPA’s Science Advisory  Board), and public comments.
EPA’s principal concern regarding criteria pollutants is for noncancer  health effects.  In contrast to most other EPA noncancer risk  assessments, however, EPA does not apply a threshold approach in the  case of criteria pollutants.  Instead, the agency models response curves  as though they have no threshold, recognizing that, as a practical matter,  at least some members of the general population will have their  thresholds exceeded at or near the lowest exposure levels.  EPA  characterizes these response relationships without any conservative  upper-bound methods.  However, probabilistic methods are used to  characterize uncertainty in the fitted exposure-response relationships.   In addition, there is temporal variation in pollution concentrations, so  characterization of exposure-time relationships is also an important  component of EPA’s assessments of criteria pollutants.
Although EPA’s exposure assessments (and risk characterization) for  criteria pollutants focus on population risks, rather than individual  risks, the agency does consider effects on more sensitive or exposed  populations.  Exposure assessments are also affected by the need to  establish air quality standards for both annual and daily concentrations  for some pollutants.  The annual standards are intended to provide  protection against typical day-to-day exposures as well as longer-term  exposures, while the daily standards are intended to provide protection  against days with high peak concentrations of pollutants.  EPA’s  exposure assessments therefore need to address these types of  variations.  Rhomberg noted that, because of the long history of analysis  of standard pollutants, EPA’s exposure modeling has been continually  improved and expanded, resulting in sophisticated models with  capabilities well beyond models used in other situations that do not  have the benefit of decades of experience and application.
Finally, it is important to recognize that one of the most important uses  of risk assessments regarding criteria air pollutants is to characterize  the population exposure levels and health effects that would be  expected given various specified air quality criteria.  In other words, one  of the primary uses of risk assessment is to estimate what the effects  would be if standards were set at various specified levels, rather than  using the tool simply to estimate what health risks these pollutants pose.
Hazardous air pollutants (air toxics)
Although the Clean Air Act Amendments of 1990 shifted the focus in  hazardous air pollutant regulation to technology-based controls, several  activities may still involve risk assessments, including  listing and delisting of hazardous air pollutants, which depends on  whether a chemical may present a threat of adverse effects to  humans and the environment;  de minimis delisting of source categories, which requires sources be  listed unless they pose less than a 10-6 risk to the maximally exposed  individual (MEI);  triggering the consideration of further regulation to address residual  risks that remain after applying MACT standards (triggered if the MEI  suffers a 10-6 or greater lifetime risk); and  offset trading of one pollutant for another based on whether the  increase in emissions is offset by an equal or greater decrease in a  “more hazardous” air pollutant.
According to section 112(o) of the amended CAA, prior to the  promulgation of any residual risk standard, EPA shall revise its  guidelines for carcinogen risk assessment or provide an explanation of  the reasons regarding any NAS report section 112(o)(4)  recommendations that have not been implemented.
The amended act also had a major impact on hazard identification for  air toxics.  The amendments defined hazardous air pollutants as air  pollutants listed pursuant to section 112(b) of the act.  Section 112(b)  included an initial list of 189 compounds incorporated by reference into  the law.
Dose-response analysis for air toxics has in the past been done largely  through Health Assessment Documents produced by ORD for the air  office, according to the methods discussed in the earlier section on EPA- wide risk assessment procedures.  Carcinogen potency calculations for  de minimis delisting and residual risk determination will be done under  the revised carcinogen assessment guidelines, once they are finalized.   EPA addresses noncancer risks for hazardous air pollutants with its  usual methodologies (e.g., NOAEL/LOAEL, benchmark dose, or others).
With the 1990 amendments, exposure assessments for air toxics will  focus on assessing the residual risk for the most exposed individual  after MACT has been applied.  OAR uses a population-based risk  assessment to generate estimates of how risks are distributed within the  population, not just for specific conservative scenarios.  According to  Rhomberg (and confirmed by OAR officials), OAR’s intent is to define  the actual most exposed person in the population, rather than a  hypothetical person with an unrealistically high estimated exposure.   EPA has adopted a tiered approach to analyzing residual risk consistent  with the recommendations from NAS and the  Presidential/Congressional Commission.  In the screening phase,  default conservative assumptions are used to ensure that risks will not  be underestimated.  Sources and hazardous air pollutants that exceed  some benchmark in the screening analysis will be evaluated further.   According to OAR, the more refined assessments will utilize more site- specific information and more realistic assumptions, especially as they  relate to exposure.  EPA estimates exposures to air toxics using a  general-purpose model largely based on fate and transport  considerations for stack emissions.   OAR officials noted that they are  updating their modeling methodology, updating their Human Exposure  Model with the current state-of-the-art dispersion model (ISCST3), and  will be updating the census data they use with the 2000 Census numbers  when they become available.
section_title: Office of Water
paragraphs: OW is responsible for the agency’s water quality activities, including  development of national programs, technical and science policies,  regulations, and guidance relating to drinking water, water quality, ground  water, pollution source standards, and the protection of wetlands, marine,  and estuarine areas.  Chemical risk assessments are associated, in  particular, with EPA’s ambient water quality criteria, under the CWA, and  drinking water quality regulations, under the SDWA.
The goal of CWA is to maintain and improve the cleanliness and biological  integrity of the nation’s waters, including lakes, rivers, and navigable  waters.  Under CWA, EPA publishes water quality criteria defining the  degree of water quality that is compatible with intended uses and states of  different water bodies.  The criteria are health based, but they are not rules  and are themselves unenforceable.  States use these criteria as guidance for  developing state water quality standards and setting enforceable limits in  permits for facilities that discharge pollutants into surface waters.  CWA  distinguishes “conventional” from “toxic” pollutants.  Toxic water  pollutants are evaluated as exposures to toxic chemicals (similar to EPA’s  treatment of hazardous air pollutants).
The goal of SDWA is to protect the quality of public drinking water systems.   The law focuses on all waters actually or potentially designed for drinking  use, whether from above ground or underground sources.  SDWA requires  EPA to set drinking water standards to control the level of contaminants in  drinking water provided by public water systems, which the water systems  are required to meet.  Congress passed extensive amendments to SDWA  through the Safe Drinking Water Act Amendments of 1996 (PL 104-182).   Among other key changes, the amendments increased regulatory flexibility,  focused regulatory efforts on contaminants posing the greatest health  risks, and added risk assessment and risk communication provisions to  SDWA.
There are several risk-related mandates in these acts.
Under CWA, EPA is to establish criteria for water quality solely on the  basis of health and ecological effects and “accurately reflecting the  latest scientific knowledge…  on the kind and extent of all identifiable  effects on health and welfare.”  CWA defines a toxic pollutant as one  that after discharge and upon exposure, ingestion, inhalation, or  assimilation into any organism, either directly from the environment or  indirectly by ingestion through food chains, will, on the basis of  information available to the Administrator, cause death, disease,  behavioral abnormalities, cancer, genetic mutations, physiological  malfunctions (including malfunctions in reproduction), or physical  deformities in such organisms or their offspring. Federal water quality  criteria are unenforceable, but states develop enforceable permit limits  based on them.
In contrast to the unenforceable federal water quality criteria, CWA also  provides for the promulgation of enforceable federal performance  standards for sources of effluent (waste discharged into a river or other  water body) that do include consideration of technological and  economic feasibility.  Since 1977, establishment of effluent standards for  toxic pollutants has been based on the best available technology (BAT)  economically achievable by particular source category.  The compounds  to be regulated are specified in a list, and there are provisions for  additions and deletions to the list.  Standards must be at that level which  the Administrator determines provides “an ample margin of safety,” so  that standards more stringent than BAT may be named at EPA  discretion.
Under SDWA, the EPA Administrator is to “promulgate national primary  drinking water regulations for each contaminant…  which…  may have  any adverse effect on the health of persons and which is known or  anticipated to occur in public water systems.”  An important feature of  such regulations, however, is that a standard specifies two levels of  contamination.  First, a maximum contaminant level goal (MCLG) is set  solely on health grounds “at a level at which no known or anticipated  adverse effects on the health of persons occur and which allows an  adequate margin of safety.”  For each such goal there is also a maximum  contaminant level (MCL).  This MCL is to be as close to the MCLG “as is  feasible,” where feasible means “with the use of the best technology,  treatment techniques and other means which…  are available (taking  cost into consideration).”  The MCL is the enforceable standard.
The 1996 amendments to SDWA added several provisions that increased  the importance of risk assessment and risk communication in EPA’s  regulation of drinking water quality.  For example, the amendments  Require EPA, when developing regulations, to (1) use the best  available, peer-reviewed science and supporting studies and data and  (2) make publicly available a risk assessment document that  discusses estimated risks, uncertainties, and studies used in the  assessment.
Require EPA to conduct a cost-benefit analysis for every new  standard to determine whether the benefits (health risk reduction) of  a drinking water standard justify the costs.
Permit consideration of “risk-risk” issues by authorizing EPA to set a  standard other than the feasible level if the feasible level would lead  to an increase in health risks by increasing the concentration of other  contaminants or by interfering with the treatment processes used to  comply with other SDWA regulations.
Require EPA to review and revise, as appropriate, each national  primary drinking water regulation promulgated by the agency at least  every 6 years.  Of particular relevance to the use of risk assessment  information, any revisions must “maintain, or provide for greater,  protection of the health of persons.”
Require EPA to identify subpopulations at elevated risk of health  effects from exposure to contaminants in drinking water and to  conduct studies characterizing health risk to sensitive populations  from contaminants in drinking water.
Additional information on major features and characteristics of chemical  risk assessments related to water quality protection activities is presented  below.
The various offices within OW—the Office of Ground Water and  Drinking Water; Office of Science and Technology; Office of  Wastewater Management; and Office of Wetlands, Oceans, and  Watersheds—have developed extensive technical and analytical  guidance on water quality monitoring and the development of water  quality criteria.  One recently finalized document particularly  relevant for describing OW’s current risk assessment procedures is  the revision to the methodology for deriving ambient water quality  criteria (AWQC) for the protection of human health.  Published  pursuant to section 304(a)(1) of the CWA, OW noted that this revised  methodology supersedes EPA’s 1980 guidelines and methodology on  this subject.  In addition to describing OW’s approach to developing  new and revising existing AWQC, it defines the default factors that  EPA will use in evaluating and determining consistency of state water  quality standards with the requirements of the CWA.
Although there are different statutory bases and risk mandates for  the regulation of ambient and drinking water, OW’s risk assessment  procedures in support of CWA and SDWA are mostly similar.
However, risk assessments in support of CWA consider not just  human health effects but also the ecological effects associated with  exposure to pollutants.   With regard to human health risks, perhaps  the most notable difference between the ambient water and drinking  water parts of OW is the additional focus, during exposure  assessments for CWA purposes, on exposures to contaminated water  through consumption of contaminated fish or shellfish.  (This is a  primary reason for potential differences in the resulting drinking  water and ambient water quality criteria or standards for the same  chemical.)
OW’s Office of Science and Technology does all of the risk  assessments for SDWA maximum contaminant level goals and CWA’s  AWQC.  For cancer risk evaluation, OW has been applying the  principles in EPA’s proposed revision of the carcinogen guidelines.
For hazard identification purposes, SDWA originally had specified a  list of compounds to be regulated as toxic pollutants and required  EPA to regulate an additional 25 contaminants every 3 years.   However, the 1996 amendments eliminated that requirement and  revised OW’s approach for listing, reviewing, and prioritizing the  drinking water contaminant candidate list.  The new risk-based  contaminant selection process provides EPA the flexibility to decide  whether or not to regulate a contaminant after completing a required  review of at least five contaminants every 5 years.  EPA must use  three risk-related criteria to determine whether or not to regulate:  (1) that the contaminant adversely affects human health; (2) it is  known or substantially likely to occur in public water systems with a  frequency and at levels of public health concern; and (3) regulation of  the contaminant presents a meaningful opportunity for health risk  reduction.  The 1996 amendments also included specific  requirements to assess health risks and set standards for arsenic,  sulfate, radon, and disinfection byproducts.
There are a number of important features regarding OW’s exposure  assessments in support of CWA and SDWA regulations.
OW’s primary exposure question during the criteria/standard-setting  process for drinking or ambient water is hypothetical: What health  effects might be expected if people consumed water and/or finfish  and shellfish contaminated at the level of a candidate standard?  The  main function of exposure assessment is to link criteria or water  concentrations to doses of chemicals and the associated health  effects that might be projected.
For its exposure assessments, OW uses estimates of water and food  ingestion in the United States based on a variety of surveys and  studies.  One of the major sources of per capita water and fish  ingestion is the Department of Agriculture’s Continuing Survey of  Food Intakes by Individuals (CSFII), which presents results for the  general population and for certain subpopulations (e.g., pregnant and  lactating women, children).
For assessing standards under SDWA, the linking of water  concentration to dose is conducted through standardized  consumption values.  For example, the default exposure scenario of  lifetime consumption by individuals is 2 liters of water per day.   However, OW uses other default values to address consumption by  sensitive subpopulations, especially children and infants.  For  assessing AWQC under the CWA, EPA uses the same water  consumption rate as under SDWA.  In addition, though, the agency  adds the dose resulting from the daily average consumption of 17.5  grams of fish.
An important change in EPA’s approach for developing AWQC,  reflected in the 2000 Human Health Methodology, has been the  move toward use of a bioaccumulation factor (BAF) to estimate  potential human exposure to contaminants via the consumption of  contaminated fish and shellfish.  BAFs reflect the accumulation of  chemicals by aquatic organisms from all surrounding media (e.g.,  water, food, and sediment).  EPA’s 1980 method used a  bioconcentration factor that reflected only absorption directly out of  the water column, and therefore tended to underestimate actual  contaminant levels in fish and shellfish.  EPA’s revised methodology  also gives preference to the use of high-quality field data over  laboratory or model-derived estimates of BAFs.
OW considers indirect exposures to a substance from sources other  than drinking water (e.g., food and air) when establishing AWQC.   This is particularly important for noncarcinogens, where the fact that  several exposure sources might individually be below the RfD level  does not mean that collectively the exposure is below this  presumably safe level.  OW has revised and expanded its policy on  accounting for nonwater sources of indirect exposures known as the  “relative source contribution.”  The procedures for calculating the  relative source contribution vary depending on the adequacy of  available exposure data, levels of exposure, sources and media of  exposure relevant to the pollutant of concern, and whether there are  multiple health-based criteria or standards for the same pollutant.   (See table 5 in the next section for a more detailed description of  these assumptions.)
section_title: Risk Assessment Assumptions and Methodological Choices
paragraphs: EPA’s risk assessment guidelines and other related documents identify  many default assumptions, standardized data factors, and methodological  choices that may be used in chemical risk assessments.  As pointed out by  NAS, assumptions and professional judgment are used at every stage of a  risk assessment, because there are always uncertainties in risk  assessments that science can not directly answer.  For the most part, these  assumptions and choices are intended to address various types of  uncertainties—such as an absence or limited amount of available data,  model uncertainty, and gaps in the general state of scientific knowledge— or variability in the population.  They are also intended to provide some  consistency and transparency to agency risk assessments.  Defaults are  generally used in the absence of definitive information to the contrary, but  also reflect policy decisions.
In its guidelines, EPA characterizes many of its choices as conservative or  public-health protective in that they are intended to help the agency avoid  underestimating possible risks.  Agency guidelines often cited the scientific  studies and other evidence that supported the agency’s choice and the  plausibility of the resulting risk estimates.  In our recent report on EPA’s  use of precautionary assumptions, we identified three major factors  influencing the agency’s use of such assumptions: (1) EPA’s mission to  protect human health and safeguard the natural environment (including  specific requirements in some of the underlying environmental statutes),  (2) the nature and extent of relevant data, and (3) the nature of the risk  being evaluated.
EPA’s program offices commonly employ tiered risk assessment  approaches that progress from rough screening assessments (for which  only limited data may be available) through increasingly detailed and  rigorous analyses, if needed.  EPA’s guidelines and program-specific  documents indicate that conservative default assumptions are most often  used during initial screening assessments, when the primary task is to  determine whether a risk might exist and further analysis is called for.   Such screening assessments may use “worst case” assumptions to  determine whether, even under those conditions, risk is low enough that a  potential problem can be eliminated from further consideration.  According  to guidelines and related descriptive materials from the program offices,  conservative assumptions are used less often in later tiers, as the agency  attempts to gather and incorporate more detailed data into its analyses.
Several circumstances may lead to conservative choices playing a less  prominent role in EPA risk assessments.  For example, the development of  more complex and sophisticated models for cancer and noncancer effects  places more emphasis on using the full range of available data and  characterizing the full range of potential adverse outcomes and effects.   Similarly, the increased use of probabilistic analytical methods to derive  parameter values will tend to reduce the “compounding” effect of picking  conservative point values for each factor.  As noted above, the use of tiered  risk assessment approaches may also limit the use of default assumptions if  more rigorous and case-specific analysis is done beyond initial screening  assessments.  However, all of these developments may require substantial  additional effort and the availability of considerable data, which might not  be possible in many cases.
Although not intended to be comprehensive, table 5 illustrates in detail  some of the specific assumptions, default data values, or methodological  choices that are used in EPA chemical risk assessments.  The table  concentrates primarily on default choices from EPA’s various agencywide  risk assessment guidelines.  However, to also provide a sense of how  default choices are used at the program level, we have included examples  of standard assumptions and values employed by two of EPA’s program  offices.  One set of examples illustrates assumptions and choices used by  OPP.  The second set presents more detailed descriptions of the standard  assumptions and choices identified in OW’s risk assessment methodology  for deriving AWQC for the protection of human health.  OW’s policy reflects  many of the same basic choices that would apply to assessments  conducted across the agency, such as the use of uncertainty factors when  estimating an RfD.
To the extent that EPA’s documents identified for each of these  assumptions or choices a reason for its selection, when it would be applied  in the risk assessment process, and its likely effect on risk assessment  results, we have reported that information.  However, it is important to  recognize that there is no requirement that agencies provide such  information in their guidelines (or even that they have guidelines).  In  particular with regard to the “likely effects” column, EPA officials  cautioned that it is not always appropriate to characterize a single  assumption separate from the rest and that it is not always possible to  quantify the effect of each default assumption.  They noted that, in general,  their default assumptions are intended to be public-health protective.
The information presented in table 5 was taken primarily from EPA risk  assessment guidelines and related documents but also reflects additional  comments provided by EPA officials.  (GAO notes and comments appear in  parentheses.)
section_title: Risk Characterization
paragraphs: As with exposure assessment, the program offices typically are responsible  for completing the risk characterization.  EPA does, however, have several  documents that provide agencywide guidance on how such  characterization is to be done.  The guidance includes a February 26, 1992,  memorandum from the EPA Deputy Administrator entitled, “Guidance on  Risk Characterization for Risk Managers and Risk Assessors,” and a March  21, 1995, document issued by the EPA Administrator entitled, “Policy for  Risk Characterization at the U.S. Environmental Protection Agency.”  EPA  also has developed a Risk Characterization Handbook to provide more  detailed guidance to agency staff.
In the statement accompanying its 1994 report Science and Judgment in  Risk Assessment, NRC said that although EPA’s overall approach for  assessing risks was fundamentally sound, the agency “must more clearly  establish the scientific and policy basis for risk estimates and better  describe the uncertainties in its estimates of risk.”  In March 1995, the EPA  Administrator issued the agency’s risk characterization policy and  guidance, which reaffirmed the principles and guidance in the agency’s  1992 policy. EPA’s guidance document defined risk characterization as the  final step in the risk assessment process that (1) integrates the individual  characterizations from the hazard identification, dose-response, and  exposure assessments; (2) provides an evaluation of the overall quality of  the assessment and the degree of confidence the authors have in the  estimates of risk and conclusions drawn; (3) describes the risks to  individuals and populations in terms of extent and severity of probable  harm; and (4) communicates the results of the risk assessment to the risk  manager.  Discussing “guiding principles” for risk characterization, EPA  emphasized that the integration of information from the three earlier stages  of risk assessment, discussion of uncertainty and variability, and  presentation of information to risk managers requires the use of both  qualitative and quantitative information.  For example, when assumptions  are made in exposure assessment, EPA said that the source and general  logic used to develop the assumptions should be described, as well as the  confidence in the assumptions made and the relative likelihood of different  exposure scenarios.
In the 1995 policy statement, EPA said that risks should be characterized in  a manner that is clear, transparent, reasonable, and consistent with other  risk characterizations of similar scope. EPA said that all assessments  “should identify and discuss all the major issues associated with  determining the nature and extent of the risk and provide commentary on  any constraints limiting fuller exposition.”  The policy also said risk  characterization should (1) bridge the gap between risk assessment and  risk management decisions; (2) discuss confidence and uncertainties  involving scientific concepts, data, and methods; and (3) present several  types of risk information (i.e., a range of exposures and multiple risk  descriptors such as high ends and central tendencies). The policy stated  that each risk assessment used in support of decision making at EPA  should include a risk characterization that follows the principles and  reflects the values outlined in the policy.  However, the policy statement  went on to say that it and the associated guidance did not establish or  affect legal rights or obligations.
Some of EPA’s other risk assessment guidelines also discuss and  recommend certain approaches to the risk characterization phase.  For  example, EPA’s proposed guidelines for carcinogen risk assessment call for  greater emphasis on the preparation of “technical” characterizations to  summarize the findings of the hazard identification, dose-response  assessment, and exposure assessment steps.  The agency’s risk assessors  are then to use these technical characterizations to develop an integrative  analysis of the whole risk case.  That integrative analysis is in turn used to  prepare a less extensive and nontechnical Risk Characterization Summary  intended to inform the risk manager and other interested readers.  EPA  identified several reasons for individually characterizing the results of each  analysis phase before preparing the final integrative summary.  One is that  the analytical assessments are often done by different people than those  who do the integrative analysis.  The second is that there is very often a  lapse of time between the conduct of hazard and dose-response analyses  and the conduct of the exposure assessment and integrative analysis.   Thus, according to EPA, it is necessary to capture characterizations of  assessments as the assessments are done to avoid the need to go back and  reconstruct them.  Finally, several programs frequently use a single hazard  assessment for different exposure scenarios.  The guidelines also point out  that the objective of risk characterization is to call out any significant  issues that arose within the particular assessment being characterized and  inform the reader about significant uncertainties that affect conclusions,  rather than to recount generic issues that are covered in agency guidance  documents.
In another example, EPA’s ecological risk guidelines emphasize that risk  characterization is a means for clarifying relationships between stressors,  adverse effects, and ecological entities.  In addition, this phase of the risk  assessment process is a time to reach conclusions regarding the  occurrence of exposure(s) and the adversity of existing or anticipated  effects.  Specifically, EPA guidance describes three ecological risk  characterization activities: (1) risk estimation (i.e., integrating exposure  and effects data and evaluating uncertainties); (2) risk description (i.e.,  interpreting and discussing available information about risks to the  assessment endpoints); and (3) risk reporting (i.e., estimating risks  indicating the overall degree of confidence in such estimates, citing lines of  evidence to support risk estimates, and addressing assumptions and  uncertainties).  Similar to EPA-wide guidance on risk characterization,  EPA’s ecological risk characterization guidelines emphasize open  communication with risk managers and other interested parties to clearly  convey information needed for decision making in a risk management  context.
It is also EPA’s policy that major scientifically and technically based work  products related to the agency’s decisions normally should be peer  reviewed to enhance the quality and credibility of the agency’s decisions.   With regard to EPA’s chemical risk assessments, peer review can be used  for evaluating both specific assessments and the general methods EPA uses  in its risk assessments.  Peer review generally takes one of two forms:  (1) internal peer review by a team of relevant experts from within EPA who  have no other involvement with respect to the work product that is to be  evaluated or (2) external peer review by a review team that consists  primarily of independent experts from outside EPA.  In December 2000,  EPA released a revised edition of its Peer Review Handbook for use within  the agency.
section_title: Chemical Risk Assessment at the Food and Drug Administration
paragraphs: The Food and Drug Administration (FDA) within the Department of Health  and Human Services regulates the safety of a large number and wide  variety of consumer products, including foods, cosmetics, human and  animal medicines, medical devices, biologics (such as vaccines and blood  products), and radiation-emitting products (such as microwave ovens).   Chemical risk assessments are primarily conducted by three of FDA’s five  product-oriented centers—the Center for Food Safety and Applied  Nutrition (CFSAN), the Center for Veterinary Medicine (CVM), and the  Center for Devices and Radiological Health (CDRH).  The chemical risk  assessment activities of these centers vary depending on factors such as  the underlying statutory requirements, the substances being regulated,  whether cancer or noncancer effects are of concern, and whether a  product is under pre- or postmarket scrutiny.  FDA officials said that the  agency generally follows the National Academy of Sciences’ (NAS) four- step risk assessment process, although it has not developed written  internal guidelines.  FDA often incorporates conservative assumptions into  its assessments when information essential to a risk assessment is not  known, but such assumptions are supposed to be scientifically plausible  and consistent with agency regulations or policies.  For example, CFSAN  assumptions are expected to be reasonably protective of human health.   FDA does not have an official policy on how risk assessment results should  be characterized and communicated to policymakers and the public.   However, FDA officials said that, in practice, they use a standard approach  that typically highlights the assumptions with the greatest impact on the  results of an analysis, states whether the assumptions used were  conservative, and shows the implications of different choices.
subsections: section_title: Context for FDA Chemical Risk Assessment
paragraphs: FDA’s regulatory authority is primarily derived from the Federal Food,  Drug, and Cosmetic Act, as amended (FFDCA), although several related  public health laws (e.g., the Food and Drug Administration Modernization  Act of 1997, or FDAMA) provide additional authority.  FDA administers its  regulatory responsibilities through its five product-oriented centers: (1)  CFSAN, (2) CVM, (3) CDRH, (4) the Center for Drug Evaluation and  Research, and (5) the Center for Biologics Evaluation and Research.  FDA  officials said that, although each of these five product centers conducts  some type of risk assessments, the first three primarily conduct the  chemical risk assessments that are the focus of this report. Each of these  centers has different responsibilities, authorities, and constraints on its  regulatory and risk assessment activities.
CFSAN is responsible for the regulation of food additives, color  additives used in food, and cosmetic additives.  Under the FFDCA, the  regulation of substances intentionally added to food or used in contact  with food must be based solely on the safety of the substances for their  intended uses (i.e., consideration of benefits and costs is not allowed).   A food containing an unapproved food or color additive is considered  “unsafe” unless FDA issues a regulation approving its use or, in the case  of a food contact substance, there exists an effective notification.  To  obtain an authorizing regulation or an effective notification, the sponsor  of a food or color additive must show that it is safe for its intended use.   FDA regulations under the FFDCA define a product as safe if there is “a  reasonable certainty in the minds of competent scientists that the  substance is not harmful under the intended conditions of use.”  For  food additives and color additives that are not themselves carcinogenic  but contain carcinogenic impurities, CFSAN uses a quantitative risk  assessment to determine whether the risk posed by a carcinogenic  impurity is acceptable (i.e., a lifetime risk below one per million) under  the FFDCA’s general safety clause of “reasonable certainty of no harm.”   Nevertheless, if the food or color additive itself is a known carcinogen,  under the “Delaney Clause” amendments to FFDCA, it cannot be  deemed safe and is prohibited from use in food.  CFSAN is also  involved with substantial activities in the area of postmarket concerns  with contaminants and naturally occurring toxicants.  For example, in  the past year, CFSAN participated in a number of major, international  chemical risk assessments in the areas of dioxins and various  mycotoxins.
CVM’s primary role is to implement the FFDCA requirement that animal  drugs and medicated feeds are safe and effective for their intended uses  and that food from treated animals is safe for human consumption.   Under the FFDCA, the regulation of residues of animal drugs that  become a part of food because of the use of the animal drug must be  based solely on health factors (i.e., consideration of benefits and costs is  not allowed).  A carcass or any of its parts that contain residues of an  unapproved drug, or residues of an approved drug above approved  levels, is considered to be unsafe and the carcass is considered  adulterated.  CVM uses risk assessment to help develop safe  concentration levels in edible tissues, residue tolerances for postmarket  monitoring, and withdrawal periods for slaughter following drug  treatment.  For noncancer effects, the applicable safety standard under  FFDCA is that that these concentrations, tolerances, and withdrawal  periods should represent a “reasonable certainty of no harm.”  FFDCA  includes provisions that permit FDA to authorize extralabel uses of an  animal drug that would pose a “reasonable probability” of risk to human  health if residues of the drug are consumed.  The agency may establish a  safe level for the residue and require that the drug sponsor provide an  analytical method for detecting residues of such a compound.   However, the act prohibits use in food-producing animals of any  compound found to induce cancer when ingested by people or animals  unless it can be determined that “no residue” of that compound will be  found in the food produced from those animals under conditions of use  reasonably certain to be followed in practice.  FDA has interpreted the  intention of the “no residue” language in the statute as meaning that any  remaining residues should present an insignificant risk of cancer to  people.  As a matter of policy, FDA accepts a lifetime risk below one per  million as an insignificant level.
CDRH administers the medical device provisions of FFDCA, and  assesses risks posed by chemicals that might leach out from medical  devices (e.g., breast implants) into surrounding tissue.  The center’s  basic mission is to protect the public health by ensuring that there is  reasonable evidence of the safety and effectiveness of medical devices  intended for human use.  CDRH usually evaluates risks in the context of  a premarket review system, and the decision to clear or approve a  product to treat a specific condition is based on a benefit-risk analysis  for the intended population and use (not just on the basis of safety or  human health as in the case of food regulation).  Because all medical  products are associated with risks, CDRH considers a medical product  to be safe if it has reasonable risks given the magnitude of the benefit  expected and the alternatives available.
Another unit of FDA, the National Center for Toxicological Research  (NCTR), has an important supporting role in the risk-related activities of  the product centers.  NCTR conducts much of the agency’s methodological  research on risk assessment methods and helps to develop and modify  FDA’s quantitative methods, in conjunction with experts from the various  product centers.  NCTR also provides toxicology research supporting all  components of FDA.  It performs fundamental and applied research  designed specifically to define biologic mechanisms of action underlying  the toxicity of products regulated by FDA.
section_title: Risk Assessment Procedures
paragraphs: Although FDA has long been a pioneer in the development of risk  assessment methods, the agency has not developed written internal  guidance specifically on conducting risk assessments.   FDA officials  noted that much of their work is done before products are placed on the  market and, in those instances, the burden of proof is on sponsors seeking  FDA approval for new products.   The documents are meant to represent the  agency’s current thinking on the scientific data and studies considered  appropriate for assessing the safety of a product.  However, the guidance  documents are not legal requirements and do not preclude the use of  alternative procedures or practices by either FDA or external parties.   Some of these guidelines include detailed descriptions of risk assessment  methods deemed appropriate to satisfy FDA’s reviews under various  statutory provisions.   FDA has also adopted a number of domestic and  international consensus standards that prescribe certain risk assessment  methods (e.g., approaches for assessing the safety of medical devices and  default consumption values for meat products).
This is not true with regard to dietary supplements.  The Dietary Supplement Health and  Education Act of 1994 created a new framework for FDA’s regulation of dietary  supplements, which do not have to undergo preapproval by FDA to determine their safety or  efficacy.  FDA officials said they currently have no standard procedures for dietary  supplement risk assessment.
FDA risk assessment procedures have also been described by individuals  and organizations from within and outside of the agency in scientific and  professional journal articles.  For example, a 1997 journal article written by  a panel of officials from across FDA summarized the risk assessment  approaches of each of FDA’s product centers.  A 1996 report on federal  agencies’ chemical risk assessment methods described CFSAN’s methods,  but did not describe the approaches used by the other centers within  FDA.  FDA’s food safety risk assessment procedures were also described  in “Precaution in U.S. Food Safety Decisionmaking: Annex II to the United  States’ National Food Safety System Paper,” which was prepared for the  Organization for Economic Cooperation and Development in March 2000.
FDA officials said that the agency generally follows the four-step risk  assessment process identified by NAS: hazard identification, dose-response  assessment (which FDA prefers to call “hazard characterization”),  exposure assessment, and risk characterization.  They said that they also  rely on past precedent and other seminal works on risk assessment, such  as the 1985 Office of Science and Technology Policy guidance document on  cancer risk assessment.  However, they emphasized that FDA does not  presume there is a “best way” of doing a risk assessment and is continually  updating its procedures and techniques with the goal of using the “best  available science.”
subsections: section_title: Differences in Risk Assessment Among FDA Product Centers
paragraphs: FDA officials also said that there are variations in the risk assessment  approaches used among the agency’s different product centers and, in  some cases, within those centers.  In general, those variations are traceable  to differences in the following factors:  the substances being regulated,  the nature of the health risks involved (particularly carcinogens versus   statutory and regulatory requirements,  whether the risk assessment is part of the process to review and  approve a product before it can be marketed and used (premarket) or  whether the assessment is for risks that might arise during monitoring  of a product once it is being used (postmarket), and  the nature and extent of the scientific information available.
The nature and extent of scientific information varies on a case-by-case  basis.  The other factors, however, are more generic, and table 6 illustrates  how they are similar or different across CFSAN, CVM, and CDRH.  The  subsections following the table describe more specifically how CFSAN,  CVM, and CDRH conduct the first three stages of risk assessment.
CFSAN’s procedures for hazard identification and dose-response  assessment vary depending on whether noncancer or cancer risks are at  issue.  For noncancer effects, CFSAN starts with the largest dose in a  chronic animal study that did not appear to lead to an increase in toxic  effects above the level measured in unexposed control animals— the “no  observed adverse effect level” or NOAEL.  CFSAN then divides this  NOAEL by one or more safety factors to arrive at an “acceptable daily  intake” (ADI) intended to be an amount that can be ingested daily for a  lifetime without harm.  For example, CFSAN typically divides the NOAEL  by 10 to allow for the possibility that humans might be more sensitive to a  chemical than the experimental animals and then by another 10 to account  for the possibility that some individuals might have greater sensitivity than  others might.  Therefore, for ADIs derived from long-term animal studies,  CFSAN commonly uses a combined safety factor of 100.  Additional safety  factors may also be applied to account for long-term effects versus short- term experiments, inadequacies of the experimental data, or other  factors.
For cancer effects, CFSAN uses two different hazard assessment/dose- response approaches, depending on the nature of the products being  regulated.
For food and color additives that are themselves known carcinogens,  the Delaney provisions in FFDCA make risk assessment rather  straightforward.  If a petition to market a food ingredient contains an  adequately conducted animal cancer study, and if results of that study  indicate that the food ingredient produces cancer in animals, CFSAN  identifies the substance as a carcinogen under the conditions of the  study.  No further corroboration or weight-of-evidence analysis is  required, and there is no need for a detailed dose-response assessment,  exposure assessment, or risk characterization for the purpose of  determining a specific level of the carcinogenic substance in food that  may be considered to be safe.
CFSAN uses more elaborate procedures for known or suspected  carcinogenic impurities in food additives.  The center’s method for low- dose cancer risk estimation is similar to EPA’s method (presented in  app. II) on extrapolation for carcinogens (see fig. 3).  On the dose- response curve of tumor incidence versus dose for a chemical, CFSAN  chooses a point below which the data are no longer considered reliable,  usually in the range of a tumor incidence of 1 percent to 10 percent.  A  straight line is drawn from the upper-confidence limit on the estimated  risk at that point to the origin (i.e., zero incremental dose/zero  incremental response).  This provides the slope of the line used to  provide upper-bound estimates of cancer risk at low doses.  CFSAN  does not specify a particular mathematical form for the dose-response  relationship in the experimental dose range; the only requirement is an  adequate fit to the data.
According to FDA officials, CFSAN risk assessors use one of two different  methods in animal-to-human scaling when extrapolating this dose-response  curve to the estimation of upper bounds on human risk.  In one of the  methods, CFSAN assumes that cancer risks are equal in animals and  humans when doses are similar on a lifetime-averaged  milligram/kilogram/day basis (i.e., body weight scaling).  In the other  method, CFSAN bases its interspecies dose scaling on body weight to the ¾  power (in the absence of information to the contrary).  Although the  literature suggests that scaling methods can have a significant impact on  risk assessment results, FDA officials said that using one approach versus  the other makes relatively little difference. Also, because tumor rates can  be biased by intercurrent mortality in animal studies (i.e., some animals die  during the study from causes other than the tumor type being investigated),  CFSAN uses a statistical procedure to make adjustments for intercurrent  mortality in testing and estimating tumor rates.
CFSAN procedures for exposure assessments to food and color additives  are largely driven by the FFDCA requirement that the safety of a chemical  compound be assessed in terms of the total amount of the compound in the  diet.  Therefore, to determine exposure, CFSAN risk assessors must  consider all potential uses of the compound being reviewed.  Similarly, in  defining the allowable limits, the assessors must conclude that the sum  total of all of these uses is within safe limits.  CFSAN generally assumes in  its exposure assessments that the compound is present at its maximum  proposed use level in all foods in which it may be used, that any  contaminants are present at residue levels established through chemical  analysis, and that consumers are exposed to the additive every day.   Although most of the agency’s focus is on chronic (long-term) exposures,  the agency must also sometimes focus on very short-term, or even single,  exposures, especially for contaminants associated with acute toxic effects.
The first component in CFSAN’s exposure assessment for food safety is the  determination of the concentrations (i.e., use levels or residue levels, in the  case of a chemical contaminant) of a chemical in foods.  In the premarket  approval process, the sponsor of the petition or notification provides this  information.  For postmarket assessments, information may come from  focused field surveys or from established monitoring programs such as the  Total Diet Study, which has provided data since 1961 on dietary intakes of a  variety of food contaminants, including pesticides, industrial chemicals,  toxic and nutritional elements, and vitamins and radionucleides.  Analyses  are performed on foods prepared for consumption in order to provide a  realistic measure of human intake.
The second component of CFSAN’s exposure assessment is determining  the extent of consumption of different foods.  In this process, CFSAN  primarily relies on multiple-day national food consumption surveys, and  focuses on the upper end of the food intake distribution (i.e., the heaviest  consumers of particular foods).  CFSAN assumes that, within demographic  subgroups, all variation in the survey data represents variation among  individuals.  That is, the average daily consumption of a food during the  survey period is assumed to apply to that person for his or her whole life,  and the intakes for different survey participants are assumed to reflect  differences from one person to the next in each person’s lifetime  consumption.  This default assumption has acknowledged biases that  result in both overestimating high-end chronic exposures and  underestimating the proportion of the population ever consuming  particular foods.
To complete the exposure assessment, levels of an additive or contaminant  in each food type are combined with estimates of daily consumption of  each food type to give a total estimated daily intake.  FDA may calculate  exposures for various demographic groups, attempting to characterize  both a mean exposure and an exposure for the heavy consumer (typically  consumers at the 90th percentile of the intake distribution).  FDA officials  also pointed out that the exposure models they use for direct food additives  are very different from those for food-contact substances (e.g.,  packaging). For the latter, they said that the bottom line is usually a mean  exposure.
FDA officials said that for risk management purposes they may attempt to  show the implications of different scenarios used to estimate risk.  FDA  noted that a computer program that employs Monte Carlo techniques has  been developed to study the effects of variability and uncertainty of  potency and exposure estimates on estimates of risk.  Such complex  analyses have been applied principally to contaminants rather than in the  premarket evaluations for food and color additives.
subsections: section_title: CVM Risk Assessment Procedures
paragraphs: CVM uses risk assessment in both the premarket approval process and  postmarket surveillance.  Risk assessments support risk management  decisions such as the development of safe concentration values and  residue tolerances for these drugs in foods.  The primary human health  concern in chemical risk assessment for CVM is animal drug residues in  food.  Residue is defined as any compound present in edible tissues  (including milk and eggs) of the food-producing animal that results from  the use of the chemical compound, including the compound, its  metabolites, or other substances formed in or on food because of the use of  the compound.
Like CFSAN, CVM’s risk assessment procedures vary based on whether  noncancer or cancer risks are at issue.  According to FDA officials, the  center’s risk assessment procedures for noncarcinogens are similar to  those used by the rest of FDA, and are based on laboratory animal data,  estimated daily food consumption, drug and metabolite residue data, and  appropriate safety factors.  CVM’s guidelines for industry note that the  agency will calculate the ADI from the results of the most sensitive study in  the most sensitive species.  The center will normally use different safety  factors depending on the type of study supporting the ADI calculation.   When using the ADI to calculate the “safe concentration” for an animal  drug product, CVM uses standard values for residues of veterinary drugs in  edible tissues for the weight of an average adult and the amount and  proportion of meat products, milk, and eggs consumed per day.  CVM  officials pointed out that the consumption values in their guidelines for  industry are standard values used by the Joint Expert Committee on Food  Additives, sponsored by the World Health Organization and Food and  Agriculture Organization, that provides food safety recommendations to  the Codex Committee on Residues of Veterinary Drugs in Foods.
For carcinogen risk assessments, CVM uses a nonthreshold, conservative,  linear-at-low-dose extrapolation procedure to estimate an upper limit of  low-dose risk (as described under CFSAN).  Cancer risk estimates are  generally based on animal bioassays, and upper 95-percent confidence  limits of carcinogenic potency are used to account for inherent  experimental variability.  FDA officials noted that some elements and  assumptions of its dose-response analysis procedures are likely to  overestimate risk by an unknown amount.  Similarly, some of its  assumptions on exposure may also overestimate cancer risks.  For  example, CVM’s risk assessment procedures assume that the concentration  of residue in the edible product is at the permitted concentration and that  consumption is equal to that of the 90th percentile consumer.  In addition,  the agency assumes that all marketed animals are treated with the  carcinogen.  While acknowledging that all of these assumptions result in  multiple conservatisms, FDA also states that they are prudent because of  the uncertainties involved.
section_title: CDRH Risk Assessment Procedures
paragraphs: Medical devices, supplies, and implants may contain chemicals that can  leach out of the devices into surrounding tissues.  Risks from these types of  chemical contaminants are considered during the premarket review of the  material safety of a device, but concerns may also arise during CDRH’s  postmarket surveillance activities.  According to FDA officials, the  concentrations of such leachants in human tissues are generally small and  amenable to typical safety risk assessment procedures.
CDRH has issued guidance for the preclinical (premarket) biological safety  evaluation of medical devices.  In that guidance, CDRH recognizes and  uses a number of domestic and international consensus standards that  have been developed to address aspects of medical device safety, including  risks posed by exposure to compounds released from medical devices.   However, CDRH officials pointed out that they and medical device  approval applicants may use approaches other than those described in the  consensus standards to conduct risk assessments.  They said the standard  that comes closest to describing CDRH’s approach for chemical risk  assessment is International Organization for Standardization (ISO)/FDIS  10933-17.  CDRH officials noted that, although this international standard  is still in draft and has not been formally recognized by the center, the  methods that it describes represent the primary procedures used by CDRH  to assess the risk posed by patient exposure to compounds released from  medical devices.  They also pointed out that this standard is unique among  risk assessment guidelines in that it provides methods to derive health- based exposure levels for local effects such as irritation, which often  “drive” the risk assessment for compounds released from implanted  devices.
According to CDRH, hazards posed by patient exposure to a device are  typically determined after subjecting the device to a series of tests defined  by the preclinical evaluation guidance.  Evaluation of potential toxicity is  supposed to cover a number of adverse effects, including local or systemic  effects, cancer, and reproductive and developmental effects.  Unless  justification is otherwise provided, CDRH assumes that the results  obtained in animal studies are relevant for humans.  One notable exception  for medical device risk assessment, according to CDRH, is that  implantation-site sarcomas (malignant tumors) found in rodents are not  assumed to be relevant for humans.
One option available to applicants is to use a risk assessment approach  involving: (1) characterization of the chemical constituents released from a  device; (2) derivation of a tolerable intake (TI) value for the compound; and  (3) comparing the dose of each constituent received by a patient to its  respective TI value.  A TI value is a dose of a compound that is not  expected to produce adverse effects in patients following exposure to the  compound for a defined period.  According to CDRH, it is conceptually  similar to EPA’s reference dose, but different TI values can be derived for a  compound depending on the route and duration of exposure to the medical  device.
CDRH’s procedures recommend establishing TI values for noncancer  adverse effects using standard uncertainty factors in order to account for  interspecies and inter-individual differences in sensitivity.  However, CDRH  permits flexibility in the event that data are available to characterize these  uncertainties more accurately. CDRH also uses a lumped uncertainty factor  to adjust for limitations in data quality such as (1) the use of short-term  studies in the absence of long-term studies, (2) the absence of supporting  studies, and (3) use of studies involving different routes or rates of  exposure.  According to CDRH, this lumped uncertainty value typically  does not exceed 100, but can exceed 100 when acute (short-term) toxicity  data are the only basis of the calculation of a TI value for permanent  exposure.  CDRH considers this provision especially important for medical  device risk assessment because of the paucity of long-term toxicity data for  many of the compounds released from medical devices.
For carcinogenic leachants, FDA often uses low-dose linear extrapolation  techniques.  For a device-released compound that has been determined to  be a carcinogen, CDRH uses a weight-of-the-evidence approach to  determine the likelihood that it exerts its carcinogenic effect via a  genotoxic mechanism.  If the evidence suggests that the compound is  genotoxic, then CDRH uses quantitative risk assessment to estimate a TI  consistent with a risk level of 1 per 10,000.  No specific quantitative risk  assessment approaches have been identified as better than others for  conducting the cancer risk assessment.  If, however, the weight-of-the- evidence test suggests that the compound is a nongenotoxic carcinogen,  the uncertainty factor approach described above should be employed to  derive the TI.
Once the TI is derived for each compound released from a device, it is then  converted to a tolerable exposure value by taking into account the body  weight of the patient and the usage patterns of the device that releases the  compound.  Overall, the agency noted that one of the most challenging  problems in risk assessments for devices is determining the level of  exposure to leached chemicals.
section_title: Risk Assessment Assumptions and Methodological Choices
paragraphs: As previously noted, FDA does not require the use of a specific risk  assessment protocol or of specific default assumptions.  However, the  summary of FDA procedures also demonstrated that assumptions and  methodological choices are an integral part of a risk assessment.  FDA  officials noted that they employ many default assumptions or choices by  precedent.  In particular, FDA officials and several reference documents on  FDA risk assessment procedures pointed out that the agency routinely  incorporates conservative assumptions into its assessments in the face of  uncertainty.  The report on the U.S. food safety system emphasized that  precaution is embedded in the underlying statutes and the actions of  regulatory agencies to ensure acceptable levels of consumer protection.   Therefore, precautionary approaches are very much a part of the agency’s  risk analysis policies and procedures.
Although not intended to be comprehensive, the following table illustrates  in detail some of the specific assumptions or methodological choices that  are used in FDA as a whole and within particular FDA product centers.   The information in the table was taken primarily from FDA documents, but  also reflects additional comments provided by FDA officials.  (GAO notes  and comments appear in parentheses.)
section_title: Risk Characterization
paragraphs: Unlike EPA, FDA does not have an official policy on how the results of the  agency’s risk assessments should be characterized to decision makers and  the public.  However, FDA officials said that, in practice, the agency uses a  standard approach for risk characterization that is similar to EPA’s official  policy.  They said that FDA’s general policy is to reveal the risk assessment  assumptions that have the greatest impact on the results of the analysis,  and to state whether the assumptions used in the assessment were  conservative. FDA officials also said that their risk assessors attempt to  show the implications of different distributions and choices (e.g., the  results expected at different levels of regulatory intervention).  As noted  earlier, FDA may employ methods such as Monte Carlo techniques to  provide additional information on the effects of variability and uncertainty  on estimates of risk.
There are some differences in FDA risk characterization procedures  depending on the products being regulated and the nature of the risks  involved.  For food ingredients (direct and indirect food additives, color  additives used in food, and substances generally recognized as safe) and  animal drug residues that are not carcinogenic, risk characterization under  the FFDCA focuses on whether the mandate of reasonable certainty of no  harm will be achieved given the proposed limits on use and permissible  residues.  The main issue is whether the higher end (the 90th percentile) of  the distribution of estimated daily intakes is below the ADI calculated from  toxicity data.  The statutory mandate is interpreted as requiring that, for a  food additive to be declared safe, heavy consumers of particular foods  should be reasonably assured of protection even if residues were at the  maximum level allowed.  For carcinogenic impurities, FDA’s focus is also  on characterizing whether there is reasonable certainty of no harm.   However, because of the Delaney clause, risk characterization is not  needed for carcinogenic food ingredients.  Residues of carcinogenic animal  drugs are also evaluated separately under the DES proviso.
CDRH officials pointed out that the draft ISO/FDIS 10933-17 international  standard explicitly addresses one risk characterization issue—how  sensitive subpopulations should be taken into account when setting  allowable limits for compounds released from devices.  Although it states  that “idiosyncratic hypersusceptibility” should not normally be the basis of  the tolerable exposure or allowable limit, the ISO standard does not  preclude setting standards in this manner.  Furthermore, the standard says  that limits should be based on the use of the device by the broadest  segment of the anticipated user population.  Therefore, if a device is  intended for a specific population, such as pregnant women, estimates  should be based on that population.
section_title: Chemical Risk Assessment at the Occupational Safety and Health Administration
paragraphs: Although the Occupational Safety and Health Administration (OSHA)  generally follows the standard four-step National Academy of Sciences’  (NAS) paradigm for risk assessment, there are several distinguishing  characteristics of its assessments.  Under its statutory mandate, OSHA has  a specific and narrow focus on the potential risks to workers in an  occupational setting.  Further, the underlying statute and court decisions  interpreting the statute have required the agency to focus on  demonstrating, with substantial evidence, that significant risks to workers  exist before it can regulate.  In addition to presenting its own best  estimates of risk, OSHA may present estimates based on alternative  methods and assumptions.
subsections: section_title: Context for OSHA Chemical Risk Assessment
paragraphs: Much of what is distinct about risk assessment at OSHA can be traced to  statutory provisions, court decisions, and the nature of workplace  exposures to chemicals.  OSHA, an agency within the Department of Labor,  was created by the Occupational Safety and Health Act of 1970 (the OSH  Act).  The central purpose of the act is to ensure safe and healthful  working conditions.  As one of the primary means of achieving this goal,  the act authorizes the Secretary of Labor to promulgate and enforce  mandatory occupational safety and health standards.  Certain provisions  in the act stipulate both the nature and the manner in which these  standards should be established.  For example:  Under section 3(8) of the OSH Act, a safety or health standard is defined  as a standard that requires conditions, or the adoption or use of one or  more practices, means, methods, operations, or processes, reasonably  necessary or appropriate to provide safe or healthful employment or  places of employment.
According to OSHA, a standard is reasonably necessary or appropriate  within the meaning of section 3(8) if it eliminates or substantially  reduces significant risk and is economically feasible, technologically  feasible, cost effective, consistent with prior OSHA action or supported  by a reasoned justification for departing from prior OSHA actions,  supported by substantial evidence on the record as a whole, and is  better able to effectuate the act’s purposes than any national consensus  standard it supersedes.
Section 6(b)(5) of the act states that “The Secretary, in promulgating  standards dealing with toxic materials or harmful physical agents…   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 even if  such employee has regular exposure to the hazard dealt with by such  standard for the period of his working life.”
A significant factor influencing the interpretation of the OSH Act provisions  and OSHA’s approach to risk assessment is the Supreme Court ruling in its  1980 “Benzene” decision that, before issuing a standard, OSHA must  demonstrate that the chemical involved poses a “significant risk” under  workplace conditions permitted by current regulations and that the new  limit OSHA proposes will substantially reduce that risk.  This decision  effectively requires OSHA to evaluate the risks associated with exposure to  a chemical and to determine that these risks are “significant” before issuing  a standard.  However, the court provided only general guidance on what  level of risk should be considered significant.  The court noted that a  reasonable person might consider a fatality risk of 1 in 1000 (10-3) to be a  significant risk and a risk of one in one billion (10-9) to be insignificant.   Thus, OSHA considers a lifetime risk of 1 death per 1,000 workers to  represent a level of risk that is clearly significant.  The court also stated  that “while the Agency must support its findings that a certain level of risk  exists with substantial evidence, we recognize that its determination that a  particular level of risk is significant will be based largely on policy  considerations.”
Later Court of Appeals decisions have interpreted the Supreme Court’s  “Benzene” decision to mean that OSHA must quantify or explain the risk for  each substance that it seeks to regulate unless it can demonstrate that a  group of substances share common properties and pose similar risks.   Although this decision does not require OSHA to quantitatively estimate the  risk to workers in every case, it does preclude OSHA from setting new  standards without explaining how it arrives at a determination that the  standard will substantially reduce a significant risk.
According to OSHA officials, the other important contextual influence on  OSHA risk assessment is the very nature of workplace exposures to  chemicals.  Generally, workplace exposures to chemicals are at higher  levels than most environmental exposures to chemicals experienced by the  general public.  Workers are often exposed to many chemical agents at  levels not much lower than those used in experimental animal studies.   According to agency officials, this is one of the unique features of OSHA’s  chemical risk assessments.  Also, OSHA frequently has relevant human  data available on current exposures, in contrast to most other agencies  regulating toxic substances.
section_title: Risk Assessment Procedures
subsections: section_title: General Approach
paragraphs: OSHA currently has no formal internal risk assessment guidance.  Instead,  OSHA has primarily described its general risk assessment methods, as well  as the rationale for specific models and assumptions selected, in the record  of each risk assessment and regulatory action.  One reason for this,  according to agency officials, is that OSHA performs risk assessments only  for its standards.  Overall, they said the agency only publishes two or three  proposed or final rules per year, and not all of these rules involve a  chemical risk assessment.  The officials also emphasized the incremental  nature of advances in risk assessment methods and science, with  successive assessments establishing precedents for methods that may be  used for succeeding analyses.
Like EPA and FDA, OSHA uses the basic NAS four-step process for risk  assessment.  Another fundamental source for OSHA’s (and EPA’s and  FDA’s) methods was the 1985 document on chemical carcinogens produced  by the Office of Science and Technology Policy. OSHA often refers to the  reference sources of other entities, including other federal agencies, in  both specific rulemakings and as general technical links to its on-line  information on occupational risks.
Despite these common elements and procedures, several features of  OSHA’s approach differ from those of other federal agencies.  Because  OSHA does not currently have written internal guidance on its risk  assessment procedures, the information in the following sections is derived  primarily from an examination of OSHA’s chemical risk assessments.  We  also relied on secondary sources, such as Lorenz Rhomberg’s report on  federal agencies’ risk assessment methods.
section_title: Hazard Identification
paragraphs: In OSHA’s risk assessments, the hazard identification step results in a  determination that an exposure to a toxic substance causes, is likely to  cause, or is unlikely or unable to cause, one or more specific adverse health  effects in workers.  According to OSHA, this step also shows which studies  have data that would allow a quantitative estimation of risk.  OSHA defines  hazardous and toxic substances as those chemicals present in the  workplace that are capable of causing harm.  In this definition, the term  chemicals includes dusts, mixtures, and common materials such as paints,  fuels, and solvents.  OSHA currently regulates exposure to approximately  400 such substances.  In the workplace environment, chemicals pose a  wide range of health hazards (e.g., irritation, sensitization, carcinogenicity,  and noncancer acute and chronic toxic effects) and physical hazards (e.g.,  ionizing and nonionizing radiation, noise, and vibration).
Most of OSHA’s chemical risk assessments have addressed occupational  carcinogens.  In assessing potential carcinogens, OSHA may consider the  formal hazard classification or ranking schemes of other entities as part of  the available evidence on a particular chemical.  Ultimately, though, OSHA  makes its own determinations on the risk posed by particular compounds  and their classification as potential occupational carcinogens.  OSHA’s  chemical risk assessments may also discuss noncancer hazards.  For  example, in the final rule on methylene chloride the agency discussed the  evidence regarding central nervous system, cardiac, hepatic (liver), and  reproductive toxicity, as well as carcinogenicity.  Similarly, the agency’s  rulemaking on 1,3-butadiene addressed adverse health effects such as  developmental and reproductive toxicity and bone marrow effects in  addition to the evidence on carcinogenicity.  OSHA quantifies the risks of  noncancer effects if it determines that there are adequate data on exposure  and response for the substance of interest.
OSHA officials also noted that OSHA has a hazard communication  standard, which requires manufacturers, shippers, importers, and  employees to inform their employees of any potential health hazard when  handling these chemicals.  This is usually done through container labeling  and material safety data sheets.  Although this standard does not address  specific risks posed by individual chemicals, it is a comprehensive hazard  information standard for nearly all chemicals in commerce.
section_title: Dose-Response Assessment
subsections: section_title: Carcinogens
paragraphs: OSHA’s general procedures for dose-response assessment are similar to  those of EPA and FDA, especially in the choice of data sets to use for  quantitative assessments.  However, OSHA probably uses a linear low-dose  extrapolation model less often than is the case for other agencies.  OSHA  differs from the other federal regulatory agencies also in being less  conservative in setting its target risk levels when conducting low-dose  extrapolation.  As previously noted, the main points of OSHA’s risk  assessments for regulatory purposes are to determine whether significant  risks exist and to demonstrate in a broad sense the degree to which the  standard would reduce significant risk.  The specific choice of where to set  the standard is tempered by the statutory mandate that standards must be  technologically and economically feasible.
Like other agencies, OSHA states that, all things being equal,  epidemiological data are preferred over data from animal studies whenever  good data on human cancer risks exist.  More often than some other  agencies regulating exposures to toxic substances, OSHA may have  relevant human data on adverse health effects available for consideration  in its risk assessments.  However, the rulemaking examples we reviewed  also illustrate that these epidemiological data may be considered  inadequate for quantitative dose-response assessment, while animal data  may provide more precise and useful dose-response information.  In both  the methylene chloride and 1,3-butadiene dose-response assessments, for  example, OSHA had both epidemiological and animal data available, but  based its quantitative estimates on data from rodent models.  However,  OSHA did use its analysis of the epidemiological data when examining the  consistency of the results derived from animal studies.
When faced with the choice of several animal data sets, OSHA tends not to  combine tumor sites but to choose the data set showing the highest  sensitivity (i.e., most sensitive sex, species, and tumor site).  The agency  will, however, frequently present information from alternative data sets and  analyses.  The agency is likely to include benign tumors with the potential  to progress to malignancy along with malignant tumors in the data set used  for its quantitative assessments.  OSHA cited the Office of Science and  Technology Policy’s views on chemical carcinogens in support of this  practice, as well as noting that other federal agencies, including EPA and  FDA, have also included benign responses in their assessments.
Because occupational exposures tend to be closer to the range of  experimentally tested doses in animal studies, extrapolation may pose less  of a challenge for OSHA than for other regulatory agencies.  OSHA’s  preferred model for quantitative analysis of animal cancer dose-response  data and for extrapolation of these data to low doses is the “multistage  model,” which is based on the biological assumption that carcinogens  induce cancer through a series of independent ordered viable mutations,  and that cancer develops through stages.  Unlike EPA and FDA, however,  OSHA tends to focus on the maximum likelihood estimate (MLE) of the  fitted dose-response curve rather than on an upper bound, although the  agency also provides estimates for the 95-percent upper confidence limit  (UCL) of the dose-response function.  This procedure generally leads to a  less conservative risk estimate than the procedures used by EPA or FDA.
Like EPA and FDA, OSHA generally assumes no threshold for  carcinogenesis.  In contrast to the other agencies, OSHA’s default dose- metric for interspecies extrapolation is body weight scaling (mg/kg/day −  i.e., risks equivalent at equivalent body weights).  According to OSHA, this  default is used to be consistent with prior chemical risk assessments, but it  also reflects a conscious policy decision that its methodology should not be  overly conservative.  OSHA says it may in the future move to ¾ -power  scaling, as agreed to by EPA, FDA, and the Consumer Product Safety  Commission some years ago.  OSHA also says it is currently considering  developing a different form of the multistage model, which will provide  more stable MLE estimates than does the current form.
OSHA also considered data from physiologically based pharmacokinetic  (PBPK) models in the risk assessment examples we reviewed.  PBPK  models provide information on target organ dose by estimating the time  distribution of a chemical or its metabolites through an exposed subject’s  system.  OSHA noted that PBPK modeling can be a useful tool for  describing the distribution, metabolism, and elimination of a compound of  interest under conditions of actual exposure and, if data are adequate, can  allow extrapolation across dose levels, routes of exposure, and species.  In  particular, pharmacokinetic information is useful in modeling the  relationship between administered doses and effective doses as a function  of the exposure level.  However, PBPK models are complicated and  require substantial data, which may not be available for most chemicals.   OSHA pointed out in the methylene chloride rule that differences in the risk  estimates from alternative assessments (including those submitted by  outside parties) were not generally due to the dose-response model used,  but to whether the risk assessor used pharmacokinetic modeling to  estimate target tissue doses and what assumptions were used in that  modeling.
In the methylene chloride standard, OSHA developed a set of 11 criteria to  judge whether available data are adequate to permit the agency to rely on  PBPK analysis in place of administered exposure levels when estimating  human equivalent doses.  Although it is beyond the scope of this appendix  to provide a full technical explanation of the following criteria, they do  illustrate the complex nature of PBPK analysis and, more generally, the  types of issues that risk assessors consider in weighing the available data. 1. The predominant as well as all relevant minor metabolic pathways  must be well described in several species, including humans. 2. The metabolism must be adequately modeled. 3. There must be strong empirical support for the putative mechanism of  carcinogenesis. 4. The kinetics for the putative carcinogenic metabolic pathway must  have been measured in test animals in vivo and in vitro and in  corresponding human tissues at least in vitro.5. The putative carcinogenic metabolic pathway must contain metabolites  that are plausible proximate carcinogens. 6. The contribution to carcinogenesis via other pathways must be  adequately modeled or ruled out as a factor. 7. The dose surrogate in target tissues used in PBPK modeling must  correlate with tumor responses experienced by test animals. 8. All biochemical parameters specific to the compound, such as blood:air  partition coefficients, must have been experimentally and reproducibly  measured.  This must especially be true for those parameters to which  the PBPK model is sensitive. 9. The model must adequately describe experimentally measured  physiological and biochemical phenomena. 10. The PBPK models must have been validated with other data (including  human data) that were not used to construct the models. 11. There must be sufficient data, especially data from a broadly  representative sample of humans, to assess uncertainty and variability  in the PBPK modeling.
In the 1,3-butadiene standard, which came out after the methylene chloride  standard, OSHA used these same 11 criteria to judge the adequacy of the  1,3-butadiene PBPK models for dose-response assessment.  In the  butadiene case, the PBPK models did not meet all of these criteria.
For dose-response analyses from human cancer data, OSHA tends to use  similar methodologies to the other regulatory agencies.  Mostly these are  simple linear models, such as relative risk models, and estimates of risk are  based on the MLE.
section_title: Noncancer Effects
paragraphs: No specific approach or procedure for the assessment of noncancer effects  was evident in the examples of OSHA rulemakings we reviewed.  However,  OSHA clearly considered a range of noncancer toxic effects in its analyses.   In its rulemakings, OSHA focused on describing and analyzing a variety of  relevant studies, case reports, and other information found in the scientific  literature.  Rhomberg noted that, in the past, OSHA used methods that were  comparable to those of other agencies.  However, the federal court in the  AFL-CIO v. OSHA case questioned the use of standard safety factors,  noting that “application of such factors without explaining the method by  which they were determined…  is clearly not permitted.”
OSHA has produced quantitative risk estimates for reproductive and  developmental effects (glycol ethers, 1993), heart disease and asthma  (environmental tobacco smoke, 1994), Hepatitis B virus infection  (bloodborne pathogens, 1992), tuberculosis, and kidney toxicity from  cadmium exposure.  OSHA is currently working on quantitative risk  assessments for such adverse health effects as cardiovascular disease  mortality, neural effects, asthma, and respiratory tract irritation for a  number of substances.  OSHA states that new methodology has been used  for these assessments, but review drafts were not yet ready and we cannot  comment further.
section_title: Exposure Assessment
paragraphs: Under the OSH Act, OSHA has a relatively specific and narrow focus on  exposure assessment.  OSHA’s primary focus is estimating the risk to  workers exposed to an agent for a working lifetime.  This risk is calculated  in terms of a person exposed at a constant daily exposure level for 45 years  at 5 days per workweek and 8 hours per workday.  The goal is to set  standards, in the form of permissible exposure limits (PELs), so workers  would suffer no impairment during the course of their lifetime under a  continuous exposure scenario.  Although this is a hypothetical exposure  scenario, Rhomberg observed that it is not conservative compared with the  actual distribution of exposures in the workplace.  He also noted that, in  assessing the exposures and risks associated with the new proposed  standard, OSHA assumes that the standard is applied to newly exposed  workers who will work under the new standard for their entire working  lives.  No allowance is made for the fact that current workers may already  have had exposures higher than the new standard.
Despite the primary focus on long-term working lifetime exposures, there  may also be some risks posed by acute, short-term exposures.  Therefore,  although part of OSHA’s risk assessment could focus on longer-term risks  and deal with 8-hour time-weighted average (TWA) exposure, the agency’s  analysis may also cover short-term exposure effects.  In the methylene  chloride rule, for example, OSHA set the 8-hour TWA PEL primarily to  reduce the risk of employees developing cancer, while the 15-minute short- term exposure limit (STEL) was primarily designed to protect against  noncancer risks, such as negative effects on the central nervous system.
Finally, Rhomberg pointed out the following distinct features of  occupational exposure assessments: Compared to environmental exposures, exposures in the workplace  tend to be much better defined.  The workplace is a confined setting  within which practices and behaviors tend to be standardized.   Exposure levels are often high enough to be easily measured, and many  workplaces have ongoing monitoring of environmental levels of  compounds.
section_title: Risk Assessment Assumptions and Methodological Choices
paragraphs: As previously noted, OSHA’s risk assessment procedures, including its  default assumptions and methodological preferences, tend to be  established through the precedents of prior rulemakings.  In contrast to  EPA and FDA, OSHA also appears to choose somewhat less conservative  options, even though the agency notes that Congress and the courts have  permitted and even encouraged it to consider “conservative” responses to  both uncertainty and human variability.  The Supreme Court’s Benzene  decision, in particular, affirmed that “the Agency is free to use conservative  assumptions in interpreting the data with respect to carcinogens, risking  error on the side of over-protection rather than under protection.”  On the  other hand, OSHA explicitly stated in rulemakings that it takes various  steps to be confident that its risk assessment methodology is not designed  to be overly conservative (in the sense of erring on the side of  overprotection).  Although not intended to be comprehensive, table 8  illustrates some of the specific assumptions or methodological choices  used by OSHA.  It also illustrates the overt balancing of more and less  conservative choices that characterizes OSHA’s approach to risk  assessment.  The information presented in table 8 was taken primarily from  OSHA risk assessment documents but also reflects additional comments  provided by OSHA officials.  (GAO notes and comments appear in  parentheses.)
section_title: Risk Characterization
paragraphs: Although OSHA does not have written risk characterization policies, recent  OSHA rulemakings showed that the agency emphasized (1) comprehensive  characterizations of risk assessment results; (2) discussions of  assumptions, limitations, and uncertainties; and (3) disclosure of the data  and analytic methodologies on which the agency relied.  Rhomberg noted  that OSHA’s usual practice is to present the results and methodological  bases of outside parties’ risk assessments for a chemical in addition to  OSHA’s own assessment, and to feature several possible bases for risk  calculation in its characterization of risks.  In checking examples of recent  OSHA rulemakings, we also observed this emphasis on showing a range of  alternative assessments, both those of external parties and OSHA’s own  sensitivity analyses.
At least three factors help to explain this proclivity to characterize risks  using different data sets, assumptions, and analytical approaches, all of  which are rooted in the statutory context for OSHA standards setting.   First, the agency’s statutory mandate, reinforced by the Supreme Court’s  Benzene decision, is that it must demonstrate “significant” risk from  workplace exposure to a chemical with “substantial evidence.”  Second, the  OSH Act directs OSHA to base health standards on the “best available  evidence” and consider the “latest scientific data.”  The third factor is that  the standard selected will be limited by consideration of its technological  and economic feasibility and cost effectiveness.  Together, these provisions  provide ample incentive to show that a compound presents a significant  risk even when using a range of alternative estimates and scientific  evidence.  (This does not preclude the agency from focusing on one  analysis as the most appropriate to support its final estimate of risk at a  particular level of exposure.)  The bottom line is that OSHA uses risk  assessment to justify a standard by showing, in general, that significant  risks exist and that reducing exposure as proposed in the agency’s standard  will reduce those risks.
In recent OSHA rulemakings, the agency devoted considerable effort to  addressing uncertainty and variability in its risk estimates.  Such efforts  included performing sensitivity analyses, providing the results produced by  alternative analyses and assumptions, and using techniques such as Monte  Carlo and Bayesian statistical analyses.  In its risk characterizations, OSHA  provided both estimates of central tendency (such as the mean) and upper  limits (such as the 95th percentile of a distribution).  In the methylene  chloride rule, OSHA noted that, in its past rulemakings, it had frequently  estimated carcinogenic potencies via the MLE of the multistage model  parameters.  However, in this particular rule it chose for its final risk  estimate to couple one measure of central tendency (the MLE of the dose- response parameters) with a somewhat conservative measure of its PBPK  output (the 95th percentile of the distribution of human internal dose).   OSHA concluded that this combination represented “a reasonable attempt  to account for uncertainty and variability.”
section_title: Chemical Risk Assessment at the Department of Transportation’s Research and Special Programs Administration
paragraphs: The chemical risk assessments conducted by the Department of  Transportation’s (DOT) Research and Special Programs Administration  (RSPA) focus primarily on acute (short-term) risks associated with  potential accidents involving unintentional releases of hazardous materials  (HAZMAT) during transportation.  As such, they are very different from  risk assessments that focus on chronic health risks.  According to agency  officials, RSPA’s assessments are done using a flexible, criteria-based  system.  RSPA’s HAZMAT transportation safety program begins with a  hazard analysis that results in material classification. There are  international standards on the transportation and labeling of dangerous  goods that classify the type of hazard associated with a given substance  (e.g., whether it is flammable, explosive, or toxic) and the appropriate type  of packaging.  Once a hazard is classified, RSPA’s analysis focuses on  identifying the potential circumstances, probability, and consequences of  unintentional releases of hazardous material during its transportation.   DOT has written principles on how the results of its risk or safety  assessments should be presented.  Those principles emphasize  transparency regarding the methods, data, and assumptions used for risk  assessments and encourage DOT personnel to not only characterize the  range and distribution of risk estimates, but also to put the risk estimates  into a context understandable by the general public.
subsections: section_title: Context for RSPA Chemical Risk Assessment
paragraphs: According to DOT officials, chemical risks may be an element of almost  any departmental risk assessment.  For example, they said that one of the  alternatives they explored regarding air bags involved potential exposure  to chemicals used in the inflation mechanism.  They also noted that Federal  Aviation Administration (FAA) safety analyses include some elements  related to potential exposures to the chemicals that are always found in  aircraft mechanisms.  However, DOT’s risk assessment most commonly  focus on chemical risks when considering the transportation of hazardous  materials. Unintentional releases of hazardous materials during  transportation, whether due to packaging leaks or transportation  accidents, may pose risks to human health and safety, the environment, and  property.  The potential consequences of such incidents include deaths or  injuries caused by an explosion, fire, or release of gases that are toxic when  inhaled.
Under the Federal Hazardous Materials Transportation Act, as amended,  the Secretary of Transportation has the regulatory authority to provide  adequate protection against risks to life and property inherent in  transporting hazardous materials in commerce.  DOT officials pointed out  that, because this act tends to be more general than those relevant to other  agencies’ regulation of risks from chemicals, it gives DOT more flexibility  to define what is “adequate” to address potential risks.  The statute directs  the DOT Secretary to designate a material or group or class of materials as  hazardous when he or she decides that transporting the material in  commerce in a particular amount and form may pose an unreasonable risk  to health and safety or property.  The Secretary is also directed to issue  regulations for the safe transportation of such materials.  The hazardous  materials regulations apply to interstate, intrastate, and foreign  transportation in commerce by aircraft, railcars, vessels (except most bulk  carriage), and motor vehicles.
The Secretary has delegated authority for implementing these hazardous  materials responsibilities to various components within DOT.  In particular,  RSPA issues the Hazardous Materials Regulations and carries out related  regulatory functions, such as issuing, renewing, modifying, and terminating  exemptions from the regulations.  The Superfund Amendments and  Reauthorization Act of 1986 mandated that RSPA also list and regulate  under the Hazardous Materials Regulations all hazardous substances  designated by EPA.  According to DOT officials, RSPA conducts most of the  department’s risk assessments regarding the transportation of chemical  hazardous materials.  RSPA and the modal administrations in DOT—FAA,  the United States Coast Guard, the Federal Motor Carrier Safety  Administration, and the Federal Railroad Administration—share  enforcement authority for hazardous materials transportation.
RSPA’s Office of Hazardous Materials Safety (OHMS) has the primary  responsibility for managing the risks of hazardous materials transportation  within the boundaries of the United States, unless such materials are being  transported via bulk marine mode (in which case the Coast Guard is  responsible).  Overall, OHMS notes that its Hazardous Materials Safety  Program and resulting regulations (1) are risk based; (2) use data,  information, and experience to define hazardous materials and manage the  risk hazardous materials present in transportation; and (3) are prevention  oriented.  Therefore, the analysis of risk is an important element of OHMS’  responsibilities.  Within OHMS, the Office of Hazardous Materials  Technology (OHMT) provides scientific, engineering, radiological, and risk  analysis expertise.
Other entities may also be involved in conducting transportation-related  chemical risk and safety assessments.  For example, OHMS sponsored a  quantitative threat assessment by the John A. Volpe National  Transportation Systems Center (the Volpe Center), which is operated by  RSPA, to determine the probability that a life-threatening incident would  occur as a result of transporting hazardous materials in aircraft cargo  compartments.  OHMS also sponsored a multiyear research effort by the  Argonne National Laboratory to characterize the risk associated with  transportation of selected hazardous materials on a national basis.
One of the most distinctive aspects regarding the regulation of hazardous  materials transportation is the role that is played by international  agreements and definitions.  Criteria for classifying and labeling dangerous  chemicals being transported have been internationally harmonized through  the United Nations Recommendations on the Transport of Dangerous  Goods.  This UN classification system is internationally recognized, and  RSPA has essentially adopted the UN recommendations into the domestic  hazardous materials regulations.  (A more detailed description of this  classification system appears in the following section.)
section_title: Risk Assessment Procedures
paragraphs: Because of the particular regulatory context in which it operates—in  particular, its focus on acute (short-term) risks associated with  transportation accidents—RSPA does not follow the four-step risk  assessment paradigm identified by NAS and used by EPA, FDA, and OSHA.   However, RSPA’s procedures do address similar generic questions, such as  whether a particular material or activity poses a threat and the likelihood  and consequences of potential accidents.  The agency uses a criteria-based  system to assess the hazards to human health and safety, property, and the  environment that are associated with potential accidents during hazardous  materials transportation.  Chemicals are identified and classified as  hazards according to a classification system in the Hazardous Materials  Regulations that is largely harmonized with internationally recognized  criteria.  The risk analyses by RSPA then focus on assessing the potential  circumstances under which exposure could occur during transportation,  their causes, consequences, and probability of occurrence.
subsections: section_title: Guidance
paragraphs: The general risk assessment procedures applicable to RSPA are found  within DOT-wide policies on conducting regulatory analyses and also in  descriptive materials about the agency’s Hazardous Materials Safety  Program.  DOT included general guidelines for conducting a risk  assessment as part of its broader Methods for Economic Assessment of  Transportation Industry Regulations (Office of the Assistant Secretary for  Policy and International Affairs, June 1982).  The DOT guidelines for risk  assessment are grouped under three major topics:  procedural guidelines that recommend formats for presentation of risk  analyses, formats for conducting risk analyses, and reporting of  assumptions and limits of analyses;  methodology guidelines that discuss some of the more frequently used  risk methods and their applicability; and  data guidelines that discuss data sources, collection and presentation of  data, and raw and derived statistics.
The primary focus of the DOT-wide risk assessment methodology and  guidelines is on estimating the risk reduction attributable to proposed  transportation safety regulations.  DOT’s guidelines are intended to be  applicable to risk assessment of hazardous material transport by any mode  as well as assessment of other types of transportation risk.  However, DOT  stated that the guidelines are not intended to be a “cookbook,” or a  prescriptive methodology, specifying each step in a risk assessment.  DOT  pointed out in the guidelines that such an approach is not desirable,  because there is no single “correct” set of methods for assessing  transportation risk.
In addition to the DOT-wide guidelines, RSPA has produced written  materials specifically on the Hazardous Materials Safety Program.  These  materials describe the role of risk assessment in the management of risks  associated with transportation of hazardous materials and the general  process used for analysis of risks, and they define risk assessment and  management terms for purposes of hazardous materials safety.  There also  are a number of general guidance documents and reports on various  aspects of hazardous materials transportation safety that provide  additional insights into the identification and assessment of risks.
section_title: Risk Assessment Approach
paragraphs: RSPA does not apply the same NAS four-step paradigm for risk assessment  as generally used by EPA, FDA, and OSHA.  According to RSPA officials,  the main reason for this difference between their risk assessments and  most of those conducted by the other three agencies is the focus of RSPA’s  assessments.  RSPA’s concerns relative to hazardous materials  transportation are primarily directed at short-term or acute health risks due  to relatively high exposures from the unintentional release of hazardous  materials.  The officials said that, in contrast, the four basic steps of the  NAS paradigm were intended to focus on chronic health risks due to long- term, low-level background chemical exposure.  The main exceptions to  this difference in general risk assessment procedures occur when other  agencies’ assessments are similarly directed at risks associated with  unintentional releases of chemicals.  In particular, RSPA officials said that  there are parallels between their risk assessment and management efforts  and those of EPA and OSHA programs that are directed at chemical  accidents.  (See, for example, the description of the risk assessment  procedures for EPA’s Chemical Emergency Preparedness and Prevention  Office in app. II.)
In sharp contrast to most of the risk assessment procedures we described  for EPA, FDA, and OSHA, toxicity is simply one of several potentially  dangerous properties of a hazardous material of concern to RSPA.  Where  toxicity is a factor, RSPA’s risk assessments tend to center on exposure  levels that pose an immediate health hazard.  This focus is reflected in the  types of chemical toxicity information that RSPA helps develop.  For  example, RSPA actively participates on a National Advisory Committee  developing Acute Exposure Guideline Levels for chemicals.  In specific  cases where chronic toxicity or environmental values play a role in RSPA  analyses, agency officials said that they rely on what EPA, FDA, OSHA, and  other agencies have developed.
Despite such differences, RSPA’s risk assessments address similar basic  issues as the chemical risk assessments of the other three agencies (e.g.,  whether a particular material or activity poses a threat and the severity and  likelihood of potential exposures).  The DOT-wide risk assessment  guidelines primarily discuss “consequence” and “probability” analyses, but  also describe a preliminary step for defining scenarios of concern  (essentially part of a hazard identification step) and a final step to  summarize results and conclusions from the preceding analyses  (essentially a risk characterization).  The Hazardous Materials Safety  Program materials outline a similar risk assessment process that  progresses from the identification of hazards to an evaluation of incident  causes, frequencies, and consequences.
subsections: section_title: Identifying Hazards
paragraphs: RSPA begins with a hazard analysis that results in material classification.   In RSPA risk assessments, hazardous materials are chemical, radioactive,  or infectious substances or articles containing hazardous materials that can  pose a threat to public safety or the environment during transport.   Hazardous materials pose this threat through chemical, physical, nuclear,  or infectious properties that can make them dangerous to transport  workers or the public.  For example, RSPA is concerned with the potential  for the unintentional release of hazardous materials to lead to adverse  outcomes such as explosions, fires, or severely enhanced fires that can  cause deaths, injuries, or property damage.  The agency is also concerned  with the potential toxic, corrosive, or infectious effects of released  materials on humans and the environment.
According to DOT officials, their hazard classification approach is a  criteria-based system that provides them considerable flexibility in their  analysis and regulation of potential hazards.  They noted that their criteria  are geared more toward the hazard a material may pose in an accident  scenario than toward a chronic health risk.  The Director of the Office of  Hazardous Materials Technology characterized this hazard classification  approach as a more open system than used in other agencies (e.g., EPA).   He explained that, in this system, any new chemical or substance that fits  within RSPA’s matrix of hazard criteria falls under the hazardous materials  transportation regulations.
Hazard identification for these assessments is based largely on  international agreements regarding transportation of dangerous goods.  Of  particular importance, there is an internationally recognized system for the  classification, identification, and ranking of all types of hazardous  materials that was created by the UN Committee of Experts on the  Transport of Dangerous Goods.  This system is revised biennially and  published as the “United Nations Recommendations on the Transport of  Dangerous Goods.”  Under this classification system, all hazardous  materials are divided into nine general classes according to physical,  chemical, and nuclear properties.  The system also specifies subdivisions  and packing group designations (that indicate a relative level of hazard) for  some classes.  (See table 9.)
These are broad categories that may include large numbers of diverse  materials.  For example, the air cargo threat assessment noted that there  were 535 different flammable liquid entries in the hazardous materials table  and more than 700 toxic material entries.  Because there are hazardous  materials with multiple dangerous properties, these classes and  subdivisions are not mutually exclusive.  Compressed or liquefied gases,  for example, also may be toxic or flammable.  The UN Committee of  Experts created more than 3,400 possible identification numbers, proper  shipping descriptions, and hazard classes to be assigned to various  hazardous material compounds, mixtures, solutions, and devices.  There  are also generic “not otherwise specified” identification numbers and  shipping descriptions that allow the material to be classed by its defined  properties.
RSPA uses essentially the same framework as the UN recommendations for  the hazard classes and packing requirements of its Hazardous Materials  Regulations.  Table 10 shows the hazard classification system in the  regulations.
The classification system in these regulations can be very detailed for some  subjects.  For example, the regulations specifically identify the types of  toxicity tests and data that should be used to determine whether something  would be classified as poisonous material (class 6, division 6.1).  The  regulations define poisonous material as a material, other than a gas, which  is known to be so toxic to humans as to afford a hazard to health during  transportation, or which, in the absence of adequate data on human  toxicity,  is presumed to be toxic to humans because it falls within one of several  specified categories for oral, dermal, or inhalation toxicity when tested  on laboratory animals; or  is an irritating material, with properties similar to tear gas, which causes  extreme irritation, especially in confined spaces.
Of particular relevance to comparisons with chemical risk assessments of  other agencies, the regulations contain precise definitions of what  constitutes oral, dermal, or inhalation toxicity for purposes of the  Hazardous Materials Regulations.  For example, one threshold for  inhalation toxicity is defined as a dust or mist with an LC for acute  toxicity on inhalation of not more than 10 mg per liter of air.  (A different  definition applies to the inhalation toxicity of a vapor.)  The regulations  also address other testing requirements and conversion factors.  The  regulations state that, whenever possible, animal test data that have been  reported in the chemical literature should be used.
The Hazardous Materials Regulations include an extensive Hazardous  Material Table with itemized information about specific hazardous  materials.  The number of HAZMAT table entries corresponds closely with  the number created by the UN.  RSPA officials noted that the number of  specific chemicals covered by the regulations is many multiples of the  more than 3,400 entries, though, because of the generic nature of the “not  otherwise specified” descriptions.  The table includes, but is not limited to,  information such as the material’s description, hazard class or division,  identification number, packing group, label codes, limits to the quantity of  the material permitted in a single package, and special provisions  concerning its transportation.  Allyl chloride, for example, is identified as a  class 3 material (flammable and combustible liquid), is in packing group I  (indicating great danger), is forbidden on passenger aircraft and rail, and  has two special provisions regarding the tanks used for transporting this  substance.  A material that meets the definition of more than one hazard  class or division, but is not specifically listed in the table, is to be classed  according to the highest applicable hazard class or division according to a  descending order of hazard.  For example, the division of poisonous gases  is ranked as a greater hazard than the division of flammable gases.
According to OHMS, the process of classifying a material in accordance  with these hazard classes and packing groups is itself a form of hazard  analysis.  Another important feature of this process is that the regulations  require the shipper to communicate the material’s hazards through the use  of the hazard class, packing group, and proper shipping name on the  shipping paper and the use of labels on packages and placards on the  transport vehicle.  Therefore, the shipping paper, labels, and placards  communicate the most significant findings of the shipper’s hazard analysis  to other parties.  This communication aspect is particularly important in  emergency response situations if an accident occurs during transport of  these materials.
The classification system, by itself, is not sufficient for all risk assessment  purposes. For example, RSPA and OHMS still need to identify potential  scenarios in which transportation accidents, spills, and leaks could occur.   As evidenced by the air cargo threat assessment, such scenarios include  the possibility that hazardous materials might be transported in a manner  not in compliance with current regulations.  Also, as emphasized in a  November 2000 report for RSPA, the hazardous materials transport system  is highly heterogeneous and complex.  The report pointed out that this  system involves not only many different materials posing a variety of  hazards (as reflected in the classification system outlined in table 9) but  also:  a chain of events involving multiple players having different roles in the  process of moving hazardous materials (such as shippers, carriers,  packaging manufacturers, freight forwarders, and receivers of  shipments) and the possibility of multiple handoffs of a material from  one party to another during transport;  several different modes of transport (principally highway, rail,  waterway, and air), with some shipments  that switch from one mode to  another during transit; and  multiple possible routes of transit.
All of these complex features might need to be considered in identifying  hazard scenarios.  However, in identifying (and analyzing) potential hazard  scenarios, RSPA and OHMS benefit from being able to use data,  information, and experience on hazardous materials transportation  incidents.  For example, risk assessors can review data from sources such  as the DOT Hazardous Materials Information System (HMIS) that  catalogues transportation-related incidents that involve a release of  hazardous materials.  An OHMS official pointed out that the agency also  uses fairly sophisticated models in analyzing various scenarios.  He said  that such models were used, for example, to provide a scientific basis for  determining evacuation zones when developing the 2000 Emergency  Response Guidebook.
section_title: Analyzing the Consequences and Probabilities of Risks
paragraphs: In contrast to the other agencies covered in this report, determining the  toxicity of a particular chemical (dose-response assessment) is not a  central focus of risk assessment in RSPA and OHMS.  Toxicity is only one  of many risk factors under consideration (and should already be addressed  through the hazard classification system).  Instead, the primary focus of  analysis is on the potential for hazardous materials to (1) spill or leak while  in transit or (2) cause, contribute to, or multiply the consequences of a  transportation-related accident.  Analysis regarding the first item is  primarily concerned with the packaging and containers used for  transportation of hazardous materials, while analysis of the second item  also considers other elements, such as the modes and routes of  transportation for these materials.  As the DOT risk assessment guidelines  state, “Hazardous materials accidents generally are transportation  accidents in which hazardous materials happen to be present.”
DOT documents use a variety of terms to describe and refer to the analysis  of hazards or risks of concern to the department and its component offices  (e.g., hazard analysis, risk analysis, threat assessment).  However, the core  of the analysis remains the same—an evaluation of the causes,  consequences, and likelihood of transportation incidents involving  hazardous materials.  The general model in DOT’s guidelines for risk  assessment of transportation activities or operations partitions the analysis  of risk into two main parts:  prediction of possible consequences in terms of loss from accidents (or,  more broadly, incidents) while transporting materials in a specified way;  and  estimation of the probabilities or frequencies of occurrence of the  consequences of such accidents (e.g., the likelihood or expected  number of accidents occurring that would result in the above loss).
For purposes of estimating the risk reduction attributable to transportation  safety regulations, the expected loss or “risk” is computed by summing the  products of each possible loss multiplied by its probability.  (In other  words, risk in this context is the probability-weighted average loss.)
According to DOT definitions, consequence analysis is the evaluation of the  severity and magnitude of impacts associated with the occurrence of  postulated accident scenarios.  For purposes of analysis, the DOT  guidelines recommend partitioning this evaluation into three segments: (1)  initiating events (i.e., causes of an accident that can result in loss), (2)  effects (i.e., the possible mechanisms by which an initiating event might  result in injury or damage); and (3) consequences (i.e., the loss of life,  injuries, property damage, or other losses expected from the effects).  The  evaluation of consequences reflects many factors, including the  characteristics of the agent involved, the type of packaging or container  used, the amount of material being transported, and the particular modes  and routes of transportation (which also affect the extent of potential  exposure by the public and environment).  DOT defines probability  analysis as the evaluation of the likelihood of individual accident scenarios  and outcomes of adverse events.  The likelihood of a particular hazard  might be expressed either as a frequency or probability.
The analyses of consequences and probabilities are based on a variety of  data sources, including, to the extent possible, “experience” data.  Among  the sources of information identified in OHMS materials to address  consequences and probabilities are:  data from the Hazardous Materials Information System (HMIS);  commodity flow surveys;  chemical substance manufacturing, use, and transportation studies;  special analyses (such as the National Transportation Risk Analysis and  Air Cargo reports mentioned earlier in this appendix, as well as  shipment counts); and  public comments on rulemakings.
Such sources can provide valuable information for risk assessment in  general and the statistical analysis of hazardous material transportation  incidents in particular.  The HMIS database provides a good illustration of  the types of baseline data available.  This database provides incident  counts according to time, transportation phase (i.e., en route from origin to  destination, loading or unloading, and temporary storage), and  transportation mode (e.g., air, highway, and rail).  For each incident, the  database includes information on the hazardous materials involved,  including the name of the chemical shipped, container type and capacity,  number of containers shipped, number of containers that fail, and the  amount of material released.  The database also contains information  concerning the occurrence of fire, explosion, water immersion,  environmental damage, and the numbers of deaths, major and minor  injuries, and persons evacuated.
However, because DOT’s risk assessments are often used to estimate the  “risk impact” of proposed regulations, the DOT guidelines caution that lack  of directly applicable experience data for assessing the impacts is probably  the rule rather than the exception.  This is because the controls provided by  the proposed regulations constitute changes from present conditions, and  experience data, by definition, relate to present conditions.  The guidelines  also emphasize that, to evaluate the impact on risk of a proposed regulation  or its alternatives, it is necessary to perform a “with and without” type of  assessment, considering the potential effects on any or all of the elements  of the risk model.
As was the case with the classification of hazardous materials and  packaging, the agency may employ criteria-based classifications of the  consequences of potential adverse events and their likelihood of  occurrence.  A 1995 guidance document illustrates how consequence and  frequency categories were combined into a “risk assessment matrix” to  assist decision makers in their risk management decisions.  (See table 11  below.)
As was the case with the three other agencies covered by our review, some  of the chemical risk assessments produced by or for DOT have begun using  more sophisticated methods and models.  For example, the Director of  OHMT characterized the National Transportation Risk Assessment study  prepared for OHMS by the Argonne National Laboratory as using state-of- the-art risk assessment techniques to characterize risks associated with the  transportation of selected hazardous materials on a national basis.  The  consequence assessments in this study employed the Chemical Accident  Statistical Risk Assessment Model that predicts distributions of hazard  zones (i.e., areas in which a threshold chemical concentration is exceeded)  resulting from hazardous material release.  That model, in turn, reflected  the input of other physical models on subjects such as hazardous material  release rates of toxic-by-inhalation materials.  The Director noted that his  office believed this study to be the first comprehensive application of these  techniques in this arena for this purpose.
section_title: Risk Assessment Assumptions and Methodological Choices
paragraphs: Although generally very structured and criteria based, RSPA’s risk  assessments for hazardous materials transportation also use assumptions.   DOT-wide guidance documents provide a general framework for the use of  assumptions.  In general, DOT guidance recognizes that assumptions may  be made when data are lacking or uncertain, or when it is necessary to limit  the scope of an analysis.  However, the assumptions, while not empirically  verifiable, are supposed to be reasonable, logically credible, and  supportable in comparison with alternative assumptions.  The DOT risk  assessment methodology guidance specifically states that every  assessment should include a list of the major assumptions, conditions, and  limitations of the risk analysis, as well as the reasons why the assumptions  were made.
As noted earlier in this appendix, RSPA has access to a number of sources  of directly relevant data and statistics on the transportation of hazardous  materials.  However, there are limitations to these systems and data.  For  example, the authors of the national transportation risk assessment for  selected hazardous materials cautioned that the information in DOT’s data  systems was not always sufficient or detailed enough to directly support a  quantitative risk assessment.  For example, incidents involving most  hazardous materials (other than gasoline-truck accidents) typically occur  too infrequently to provide statistically reliable data for directly projecting  future risks.  In his introduction to the study, the Director of OHMT also  stated that the quantitative results of this study should be used with  caution.  Specifically, he noted, “While the model of the hazardous  materials transportation system employed in this study is sophisticated, the  accuracy of the data used in the model is often less precise.  Estimates,  assumptions, and aggregate numbers have been used in many cases.”
Some of the topics that might require assumptions or choices during a  hazardous materials transportation assessment include:  the probability of the release of a hazardous material, depending on the  nature of the accident, type of material being transported, and the  containers used;   the amount of material released in an accident, depending again on  factors such as the severity of the accident, nature of the material, and  type of container, but also depending on assumptions about the size of  holes in containers;  commodity flows of the materials (e.g., modes of transportation used,  classes of rail tracks, types of highways, routing through urban and rural  areas and related population density);  the dispersion of released hazardous material, including assumptions  about climate and meteorological conditions and the type of surface  that a liquid might “pool” on if spilled;  the probability of a fire or explosion being ignited (both as a  consequence of a release or as a cause of a release); and  the extent to which humans potentially exposed to released materials  would be sheltered or protected (both within a given mode of  transportation, such as an aircraft, or external to the carrier).
In addition to these topics, RSPA sometimes uses a factor to adjust data in  the HMIS database to address underreporting.  However, RSPA officials  noted that, for certain purposes, it might be inappropriate to extrapolate  information in the database.
Although assumptions may be needed in RSPA assessments, RSPA officials  said that they do not have default assumptions for their risk assessments.   According to the officials, assumptions must be developed and described  as part of each risk assessment and are specific to the risk assessment.   RSPA officials also noted that they do not use “safety factors” in risk  assessments, but rather base their assessments on expected levels or  ranges of performance.  Therefore, unlike in the appendices on EPA, FDA,  and OSHA, we have not included a table in this DOT appendix to identify  major default choices, the reasons for their selection, when they would be  used in the process, and their likely effects on risk assessment results.   However, with regard to some of the case-specific assumptions or choices  we identified during our review, we did observe that DOT’s assessments  typically discussed the reasons for particular choices (as with the other  agencies, often citing an interpretation of related research studies).  In  some instances, information was also provided on the likely effect (e.g.,  that a particular value represented a conservative estimate or an upper  limit) or level of uncertainty (e.g., that a particular parameter value might  be high by a factor of 3 to 10 times the results from another study)  associated with choices made by the analysts.
section_title: Risk Characterization
paragraphs: DOT has explicit, written principles regarding how the results of its risk or  safety assessments should be presented.  The department’s policies  emphasize the principle of transparency and encourage agency personnel  to not only characterize the range and distribution of risk assessment  estimates, but also to put risk estimates into a context understandable by  the general public.  For example, DOT’s “risk assessment principles” state  that the risk assessment should:   make available to the public data and analytic methodology on which  the agency relied in order to permit interested entities to replicate and  comment on the agency’s assessment;  state explicitly the scientific basis for the significant assumptions,  models, and inferences underlying the risk assessment, and explain the  rationale for these judgments and their influence on the risk assessment;  provide the range and distribution of risks for both the full population at  risk and for highly exposed or sensitive subpopulations, and encompass  all appropriate risks, such as acute and chronic risks, and cancer and  noncancer risks, to health, safety, and the environment;  place the nature and magnitude of risks being analyzed in context,  including appropriate comparisons with other risks that are regulated  by the agency as well as risks that are familiar to, and routinely  encountered by, the general public, taking into account, for example,  public attitudes with respect to voluntary versus involuntary risks, well- understood versus newly discovered risks, and reversible versus  irreversible risks; and  use peer review where there are issues with respect to which there is  significant scientific dispute to ensure that the highest professional  standards are maintained.
The DOT risk assessment guidelines also state that every risk analysis  should present information on (1) quantitative estimates of risk (over the  entire range of plausible values of the developed variables, and with a “base  case” loss to provide a point of reference); (2) insights gained from  performing the analysis into the factors that most affect risk assessment  results; and (3) assumptions, conditions, and limitations of the analysis.   With regard to the third item, the guidelines specifically state that reasons  why the assumptions were made, and why the limitations of the analysis do  not significantly impact the risk estimate, should be provided.  The  guidelines also suggest two methods for treating uncertainty in a risk  analysis:  sensitivity analysis (DOT’s preferred method for treating and reporting  the impact of uncertainty), which should be conducted for each  scenario in a risk analysis; and  bounding analysis involving error propagation (requiring that each  model parameter be expressed as a distribution, or at least a variance, to  trace the implication of uncertainty for the risk estimate).
section_title: Glossary
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