Science and Judgment in Risk Assessment (1994) / Chapter Skim
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Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment
Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment
Pages 383-448
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From page 383... ...
Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect.
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From page 384... ...
384 SCIENCE AND JUDGMENT IN RISK ASSESSMENT DISCLAIMER This document is a draft working paper for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsesement or recommendation for use.
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From page 385... ...
INTEGRATING DATA FOR HAZARD ASSESSMENT 2.3. ANALYSIS OF HUMAN DATA 2.3.1.Epidemiologic Studies 2.3.1.1.
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From page 386... ...
HUMAN HAZARD CHARACTERIZATION 2.8.1. Purpose and Content of Characterization 2.8.2.
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From page 387... ...
WORKING PAPER FOR CONSIDERING DRAFT REVISIONS TO THE U.S. EPA GUIDELINES FOR CANCER RISK ASSESSMENT This working paper identifies cancer risk assessment issues that some Agency scientists have been discussing as a basis for possible proposed revisions to EPA's 1986 Guidelines for Carcinogen Risk Assessment.
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From page 388... ...
Because methods and knowledge are expected to change more rapidly than guidelines can practicably be revised, most of the Agency's development of procedures for cancer risk assessment will henceforth be accomplished through publication of technical work performed under the aegis of the Agency's Risk Assessment Forum. The technical documents of the Forum are developed by a process that engages the general scientific community with EPA scientists.
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From page 389... ...
The narrative statement provides a place to describe evidence by route of exposure and to describe the hazard assessment and dose-response implications of mechanism of action data in characterizing the overall weight of evidence about human carcinogenicity.
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From page 390... ...
One can postulate many ways to disrupt this kind of growth control circuit, including increasing or decreasing the number of signals, receptors, or transducers, or increasing or decreasing their individual efficiencies. In fact, human genetic diseases that make individuals cancer-prone involve mutations that appear to have some of these effects (Hsu et al., 1991; Srivastava, 1990; Kakizuka et al., 1991~.
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From page 391... ...
Current reasoning holds that cell proliferation which results from changes at the level of DNA sequence or DNA transcription, from changes at the level of growth control signal transduction, or from cell replication to compensate for toxic injury to tissue can begin a process of neoplastic change by increasing the number of cells that are susceptible to further events that may lead to uncontrolled growth. Such further events may include, for instance, errors in DNA replication that occur normally at a low background rate or effects of exposure to 2The term "mutations" includes the following permanent structural changes to DNA: single basepair changes, deletions, insertions, transversions, translocations, amplifications, and duplications.
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From page 392... ...
Recognition of the role of oncogenes and mutations of tumor suppressor genes has provided specific ideas about the linkage of chemical mutagenesis to the cell growth cycle. Other agents that are not mutagenic, such as hormones and other chemicals that are stimulants to cell replication (mitogens)
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From page 393... ...
A carcinogenic agent that is not mutagenic in experimental systems, but is mitogenic or affects hormonal levels or causes toxic injury followed by compensatory growth may be inferred to have effects on growth signal transduction or to have secondary carcinogenic effects. The strength of these inferences depends in each case on the nature and extent of all the available data.
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From page 394... ...
INTRODUCTION 1.1. PURPOSE AND SCOPE OF THE GUIDELINES The new guidelines will revise and replace EPA Guidelines for Carcinogen Risk Assessment published in 51 Fly 33992, September 24, 1986.
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From page 395... ...
In the absence of epidemiologic information, tumor induction in animal assays remains the best single piece of direct evidence on which to evaluate potential human carcinogenic hazard (OSTP, 1985~. Results of animal studies have to be carefully analyzed along with other relevant data (such as metabolism and pharmacokinetic data used to compare animals and humans)
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From page 396... ...
. The 1983 NRC document provided the 1986 guidelines with a thematic organization of risk assessment into hazard identification, dose-response assessment, exposure assessment, and risk characterization.
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From page 397... ...
Available data may include: long term animal cancer bioassays and human studies, physical-chemical properties of the agent and its structural relationship to other carcinogens, studies of cellular and molecular interactions and mechanisms of action, and results from toxicological tests and experiments on the bioavailability and transformation of an agent in experimental animals and humans. Hazard assessment results are summarized in a hazard characterization that conveys the nature and impact of available data and appropriate scientific inferences about human carcinogenic hazard.
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From page 398... ...
For example, in examining the issue of causation as part of human studies analyses, one uses knowledge of the biological activity of the agent in animal systems and of pertinent features of its structure, metabolism and other properties to address issues of biological plausibility of a causal hypothesis. Likewise, where there are no epidemiologic studies and one is examining relevance of animal responses to human hazard potential, one uses human data to address comparative biology of animals and humans with respect to, for instance, metabolism, pharmacokinetics, physiology, and disease history.
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From page 399... ...
An exposure assessment which includes an attribution of quantified exposure to an individual is considered more precise and will carry more weight in an evaluation of human hazard. In many epidemiologic studies, the populations are selected and studied retrospectively, and the time between exposure and observation of effects is very long because of the latency of cancer.
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From page 400... ...
2.3.2. Elements of Critical Analysis Aspects of the available human data, which are described in this section, are evaluated to determine whether there is a causal relationship between exposure to the agent and an increase in cancer incidence.
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From page 401... ...
The job-exposure matrix has been applied to occupational scenarios where at least some current and historical monitoring data exist. In examining exposure levels inferred from a job-exposure matrix, the basis of the monitoring data must be considered whether data are from routine monitoring or reflect accidental (i.e., higher than average)
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From page 402... ...
2.3.2.4. Sensitivity Epidemiologic studies which consist of a large number of individuals with sufficient exposure to a putative cancer-causing agent and adequate length of time for cancer development or detection are considered to have a greater ability to detect cancer risk.
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From page 403... ...
fParticipants at the December 4, 1992, Socie~for Risk Analysis on cancer risk assessment issues were asked to look at meta-analysis.} 2.3.2.5. Criteria for Causality A causal interpretation is enhanced for studies to the extent that they meet the criteria described below.
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From page 404... ...
The need for this summar~zafion step for human evidence and the one in Section 2.5 for experimental evidence are open questions at EPA.3 Each epidemiological study is critically evaluated for its relevance with respect to the exposure-effect relationship, exposure assessment such as intensity, duration, time since first exposure, and methodological issues such as study design, selection and characterization of comparison group, sample size, handling of latency, confounders, and bias. Following critical evaluation, the totality of the weight-of-evidence for human carcinogenicity is assessed and summarized according to one of the following four categories, which are meant to represent a judgment regarding the weight of all of the human evidence even if only one study exists on the subject.
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From page 405... ...
The plausibility of exposure-effect relationship also can be bolstered or mitigated by evidence of structure-activity relationship analysis with well characterized agents, studies of mechanism of action, understanding of metabolic pathways, and other indirect evidence relevant to human effects. A mixture (e.g., cigarette smoke, coke oven emissions)
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From page 406... ...
Time and dose-related changes in the incidence of preneoplastic and neoplastic lesions may also be helpful in interpreting responses in long-term animal studies. It is recognized that chemicals that induce benign tumors also frequently induce malignant tumors, and that certain benign tumors may progress to malignant tumors.
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From page 407... ...
For high background tumors there are varying views, some question relevance, but usually there are insufficient data about the mechanism of action to question its relevance. Others point to the fact that both humans and animals have tissues with high background rates.} Historical control data often add valuable perspective in the evaluation of carcinogenic responses (Haseman et al., 1984~.
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From page 408... ...
Answering these questions requires a body of research data beyond the data obtained in standard animal studies. Unless there are research data to establish that such tumor data at a site occur because of a mechanism-of-action that is unique to the species, strain, and sex with the high background, the tumor data are considered, as are other tumor data, in the overall weight of evidence.
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From page 409... ...
. If information on the mechanism of tumorigenesis supports the conclusion that a response seen in an animal study is unique to that species or strain, the response is considered to provide no evidence for human hazard potential (U.S.
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From page 410... ...
For chemicals with either unsatisfactory or inadequate carcinogenicity data, SAR analysis may be used to generate, bolster, or mitigate the carcinogenic concern for the chemical, depending on the strength of and confidence in the SAR analysis. In addition, SAR analysis can also serve as a guide to evaluate carcinogenic potential of untested chemicals.
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From page 411... ...
2.6.3. Metabolism and Pharmacokinetics Studies of the absorption, distribution, biotransformation and excretion of agents are used to make comparisons among species to assist in determining the implications of animal responses for human hazard assessment, to support identification of toxicologically active metabolites, to identify changes in distribution and metabolic pathway or pathways over a dose range and between species, and to make comparisons among different routes of exposure.
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From page 412... ...
Information on how particular agents are likely to cause cancer may, however, be useful for appreciating more accurately the hazard that such agents pose to humans" (L\RC, 1991~. Results from short-term toxicological tests and molecular and cellular mechanistic studies are also useful in the interpretation of epidemiological and rodent chronic bioassay data used in hazard identification and characterization.
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From page 413... ...
Short-term animal assays generally have more defined study designs to provide information about potential mechanisms of action. A large number of short-term assays examine biological activities relevant to the carcinogenic process (e.g., mutagenesis, tumor promotion, aberrant intercellular communication, increased cell proliferation, malignant conversion, immunosuppression)
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From page 414... ...
These include gene mutations and chromosomal aberrations. To be of value in cancer risk assessment, genetic toxicology data must meet the demands of scientific scrutiny.
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From page 415... ...
Because mutagenic carcinogens have been observed to induce tumors across species and at multiple sites, evidence of both mutagenicity and tumor responses in multiple species or sexes significantly increases concern for the human carcinogenic potential of an agent. Absence of mutagenicity in multiple test systems gives insight into alternative mechanisms by which non-mutagenic carcinogens may act.
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From page 416... ...
Types of information to be considered include: whether the agent is a mutagenic or a non-mutagenic carcinogen, specific effects on proto-oncogenes or tumor suppressor genes and DNA transcription, and structural or functional analogies to agents with the above effects. Information demonstrating effects on the cell cycle would include: mitogenesis, effects on differentiation, effects on cell death (apoptosis)
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From page 417... ...
Both of these science policy assumptions are supported by current knowledge of carcinogenic processes, in the absence of better data. Each assumption must be examined in substance-specific risk assessments and replaced or joined by alternative analysis when adequate scientific data exist.
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From page 418... ...
physical-chemical properties and structural or functional analogies can support inferences of potential carcinogenicity; results in a number of short-term studies that are consistent can support inferences about potential human effects; evidence of mutagenic effects on proto-oncogenes or tumor suppressor genes; evidence of effects on cell growth signal transduction affecting cell division, differentiation; or cell death; and induction of neoplastic behavioral characteristics in cells in culture or .
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From page 419... ...
Other combinations of data also may be persuasive. In prospect, continued research on the role of agents in mutations of proto-oncogenes and tumor suppressor genes and related research on receptor-mediated effects on growth control genes also may provide persuasive data.
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From page 420... ...
or other aspects of study protocol present difficulties of interpretation; or evidence of carcinogenicity is found at a single animal site in one species and sex in one or more experiments; the response is weak and without characteristics that give weight to a conclusion about potential human carcinogenicity. For example, data are inconclusive if experimental data apart from the animal response do not support any positive inference about the agent's carcinogenic potential and if the animal response has a consistent pattern of most of the following characteristics: · At least two species have been tested, and the tumor response is seen only at the highest dose, in one sex, and one species.
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From page 421... ...
2.8. HUMAN HAZARD CHARACTERIZATION Evidence from all of the elements of hazard assessment are drawn together for an overall characterization of potential human hazard as indicated in Figure 1.
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From page 422... ...
As the first step, a decision is made on whether the evidence is adequate or not adequate for characterization. "Not adequate" means that the existing data are inadequate overall to support a conclusion because either there are too few data or the data are flawed due to experimental design or conduct, or because findings are not substantial enough to support inferences either way about potential human carcinogenicity.
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From page 423... ...
The overall conclusion is noted by use of one of the following descriptors: "known," "highly likely," or "likely" to be a human carcinogen; "some evidence" or "not likely to be a human carcinogen at exposure levels studied or alternately under conditions of environmental exposure." These descriptors fall along a continuum of likelihood that an agent has human carcinogenic potential. More than one descriptor may apply to a single agent if the weight of evidence differs by route of administration.
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From page 424... ...
What are the craters for establishing them.0 Explanations of the general levels of evidence associated with descriptors in terms of the summarizations of evidence made in the course of a hazard assessment are as follows: "Known" to be carcinogenic in humans is a statement that evidence is convincing (Category 1) that the agent has observed carcinogenic effects in humans by a specified route or routes of exposure.
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From page 425... ...
the occurrence of carcinogenic effects depends on administration of the agent in a manner that has no parallel with plausible environmental exposure, e.g., injection of polymers. This descriptor is explained in the narrative statement as being applicable only to the specific exposure levels studied or environmental exposure conditions which are given in the statement.
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From page 426... ...
Compound Y Following review of all available data relevant to the potential human carcinogenic hazard of Y (CAS # 000002) , EPA concludes that Y is likely to be carcinogenic to humans by all routes of exposure.
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From page 427... ...
In risk assessments, dose and response observations from experimental or epidemiological studies are often projected to much lower exposure levels encountered in the environment.4 In addition, the mathematical models used for extrapolation are based on general assumptions about the nature of the carcinogenic process. These assumptions may be untested for the particular agent being evaluated (Kodell, in press)
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From page 428... ...
When animal studies are used, response data from a species that responds most like humans should be used, if information to this effect exists. When an agent was tested in several experiments involving different animal species, strains, and sexes at several doses and different routes of exposure, the following approach to selecting the data sets is generally used: a.
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From page 429... ...
The objective is to provide a best judgment of how to represent the observed data. Benign tumors are usually combined with malignant tumors for risk estimation if the benign tumors are considered to have the potential to progress to associated malignancies of the same histogenic origin.
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From page 430... ...
can be great, due to, for example, first pass effects and differing results from different exposure patterns. There is no generally applicable method for accounting for these differences in uptake processes in quantitative route-to-route extrapolation of dose-response data in the absence of good data on the agent of interest.
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From page 431... ...
3.2.2.3. Additional Considerations for Dose in Human Studies The applied dose in a human study has uncertainties because of the exposure fluctuations that humans experience compared with the controlled exposures
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From page 432... ...
3.3. SELECTION OF QUANTITATIVE APPROACH Because risks at relatively low exposure levels generally cannot be measured directly either by animal experiments or by epidemiologic studies of reasonable sample size, a number of mathematical models have been developed to extrapolate from high to low dose.
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From page 433... ...
Pharmacokinetic data or interspecies scaling is used to derive human-equivalent measures of the animal-administered dose. The empirical response data analyzed include tumor incidence data augmented, if possible, by incidence data on effects leading to the tumor response, e.g., DNA adduct or other effect-marker data (Swenberg, 1987~.
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From page 434... ...
Although a model may adequately fit the observed dose-response information, all models have limitations in their ability to describe the underlying processes and make projections outside the observed information. A prime consideration is the potential for model error, that is the possibility that a model might appear to fit the observed data but be based on an inadequate mathematical description of the true underlying mechanism.
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From page 435... ...
The lowest reliable area may be extended below a 1.0 percent response if based on a more powerful study, on combined studies, or on joining the analysis of tumor response data with data on other markers of effect. This lowest reliable area provides an estimate that can be used for comparision with similar analyses of the observed range of noncancer effects of an agent (USEPA, l991f)
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From page 436... ...
Instead, a "margin of exposure" presentation is made in the risk characterization. The margin of exposure in this context is the lowest reliable dose-response area from observed data divided by the environmental dose level of interest.
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From page 437... ...
that is considered to best represent the available data and best correspond to the view of the mechanism of action developed in the hazard assessment. The exploration of significant uncertainties in data for dose and response and in extrapolation procedures is part of the characterization.
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From page 438... ...
communicates the results of exposure assessment to the risk assessor, who can then use the exposure characterization, along with the characterization of the other risk assessment elements, to develop a risk characterization. In general, the magnitude, duration, and frequency of exposure provide fundamental information for estimating the concentration of the carcinogen to which the organism is exposed.
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From page 439... ...
The summary draws from the key points of the individual characterizations of hazard, dose response, and exposure analysis performed separately under these guidelines. The summary integrates these characterizations into an overall risk characterization (AIHC, 1989~.
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From page 440... ...
5.3.2. Strengths and Weaknesses The risk characterization summarizes the kinds of data brought together in the analysis and the reasoning upon which the assessment rests.
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From page 441... ...
(1990) Tumor angiogenesis: the role of oncogenes and tumor suppressor genes.
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From page 442... ...
(1991) Incorporating cell proliferation in quantitative cancer risk assessment: approaches, issues, and uncertainties.
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From page 443... ...
(1984) Use of historical control data in carcinogenicity studies in rodents.
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From page 444... ...
(1992) A reanalysis of the National Cancer Institute study on lung cancer mortality among industrial workers exposed to formaldehyde.
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From page 445... ...
(1989) Tumor suppressor genes: the puzzle and the promise.
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From page 446... ...
(1989c) Workshop on EPA guidelines for carcinogen risk assessment: use of human evidence.
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From page 447... ...
(1992a) Guidelines for exposure assessment.
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