Toxicity Testing for Assessment of Environmental Agents Interim Report (2006) / Chapter Skim
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5 Use of Data in Human Health Risk Assessment
5 Use of Data in Human Health Risk Assessment
Pages 118-148
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From page 118... ...
Given human exposure scenarios, what is the probability of adverse effects? How does risk vary across the population?
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From page 119... ...
Throughout, the chapter notes the use and limitations of toxicologic and epidemiologic data typically available for drawing conclusions about hazards, dose-response relationships, and risk based on the guidelines. The chapter focuses on current institutional practices, emphasizing those of EPA to assess environmental agents, and on the types of data generated through regulatory testing strategies, such as those discussed in Chapter 4.
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From page 120... ...
A few of the key principles used to evaluate neurotoxicity data for risk-assessment purposes are highlighted here to show what the regulatory data needs for toxicity testing are and where available data may fall short. Definition of Neurotoxic Effects EPA, IPCS, and OECD define neurotoxicity as an adverse change in the structure or function of the central or peripheral nervous system after exposure to a chemical, physical, or biologic agent.
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From page 121... ...
EPA Concern Levels EPA neurotoxicity risk assessment distinguishes among levels of concern on the basis of the magnitude of effect, the duration of exposure, and the reversibility of some neurotoxic effects. In general, there is less concern about effects that are rapidly reversible or transitory -- specifically those measured in minutes, hours, or days -- and that appear to be associated with the pharmacokinetics of the causative agent and its presence in the body.
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From page 122... ...
For example, body-weight changes can affect measurements of auditory startle, and temperature can affect conduction velocity. If several related measures in a battery of tests are affected and the effects appear to be dosedependent, the data are considered to be evidence of a direct neurotoxic effect, especially in the absence of other systemic toxicity.
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From page 123... ...
EPA states that chemical agents that produce developmental neurotoxicity at a dose that is not toxic to the maternal animal are of special concern, whereas EPA generally discounts developmental neurotoxic effects when overt maternal toxicity is moderate or greater. However, EPA cautions that current information is inadequate to assume that developmental effects at doses that cause minimal maternal toxicity result only from maternal toxicity.
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From page 124... ...
guidelines call for summarizing the evidence from the neurotoxicity database into categories of "sufficient evidence," "sufficient human evidence," "sufficient experimental animal evidence/limited human data," and "insufficient evidence." The "sufficient evidence" category includes data that collectively provide enough information to judge whether a human neurotoxic hazard could exist. The "sufficient experimental animal evidence/limited human data" category is used when the evidence is judged to support a conclusion of potential or lack of potential neurotoxic hazard.
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From page 125... ...
In 1991, EPA published Guidelines for Developmental Toxicity Risk Assessment (1991) , which outlines the principles and methods for evaluating exposure data from animal and human studies to characterize risks to human development, growth, survival, and function.
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The EU and UN systems generally require direct evidence from animal or human studies for a chemical to be placed in known, presumed, or suspect categories. Noncancer Dose-Response Assessment Risk assessments for end points other than cancer are based on the idea that there is a magnitude of exposure -- a threshold -- at or below which effects do not occur and above which they do.
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From page 127... ...
, human intraspecies variability (UFH) , extrapolation between subchronic and chronic exposure durations (UFS)
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From page 128... ...
EPA (2002a) has recognized the IPCS approach and now uses chemical-specific adjustment factors instead of default values when it finds the available data sufficient to derive them.
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From page 129... ...
The UFA is reduced because the correction with the DAF is intended to account for species pharmacokinetic differences but does not account for pharmacodynamic uncertainties in interspecies extrapolation. Uncertainty Factor for Susceptibility of the Fetus and the Young -- Application of the Food Quality Protection Act The approach of dividing the dose at which responses are observed in animals by some factor or group of factors began in the 1950s when FDA used a factor of 100 to determine allowable human daily intakes of food additives and other compounds on the basis of animal studies
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From page 130... ...
The approach considers several factors, including available human and animal data on prenatal and postnatal toxicity, the nature of the dose-response relationship, and information on the human relevance of data from animal experiments, such as pharmacokinetics, mechanism of action, and similarity of the biologic response in different species. Table 5-1 illustrates how EPA may weigh those factors in evaluating the necessary FQPA margin.
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From page 131... ...
Use of Data in Human Health Risk Assessment 131 TABLE 5-1 EPA's Weight-of-Evidence Approach for Evaluating Degree of Concern for Prenatal and Postnatal Toxicity on the Basis of Human and Animal Data Degree of Concern Increasing Weight -- Higher Decreasing Weight -- Lower Factor Degree of Concern Degree of Concern Pre- and Effects found in humans No adverse human or postnatal toxicity related to exposure animal effects associated Same types of effects seen in with exposure more then one species Similar response in young Effects of a different type with relatively shorter with greater potential recovery than in adults consequences in young than in adults Persistence or relatively longer recovery of effects in young than in adults Dose-response Effects observed at a lower Effects at higher dose in relationship dose in young than in young than in adults or adults only at high dose in NOAEL not identified presence of severe Poor data on dose-response generalized toxicity relationship Good data on dose-response relationship that allows confident identification of NOAEL or BMD Pharmacokinetics Metabolic profile indicates Metabolic profile indicates higher internal dose of lower internal dose of active moiety in young active moiety in young than in adults or in than in adults or in humans than in animals humans than in animals Mode of action Mode of action supports Evidence indicates that relevance to humans and mode of action is concern for animal findings species-specific and thus Mode of action may lead not relevant to humans to several adverse Evidence indicates that consequences in offspring humans are less sensitive than animal model Source: Adapted from EPA 2002a.
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From page 132... ...
For five pesticides, the agency applied the full FQPA factor of 10 for at least one exposure group and exposure circumstance, such as acute dietary exposure of women of childbearing age. For six pesticides, EPA applied an FQPA factor of 3.
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The current EPA (2005a) carcinogen guidelines emphasize cancer hazard identification and dose-response assessment and provide limited guidance for carcinogen exposure assessment and risk characterization.
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has general guidance to identify a chemical "known to cause cancer" or "reasonably anticipated to be a human carcinogen." The International Agency for Research on Cancer (IARC 1999) has developed more detailed guidance to categorize a chemical as a known, probable, or possible human carcinogen or as a chemical for which inadequate evidence is available or for which evidence suggests lack of carcinogenicity.
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TABLE 5-2 Level of Evidence in Carcinogen Classification Schemes or Narrative Descriptions Type of Evidence IARC EPA NTP IOM Sufficient human, sufficient animal Carcinogenic Carcinogenic Known to be Sufficient evidence to humans to humans human carcinogen of causal relationship Sufficient human Carcinogenic Carcinogenic Known to be Sufficient evidence to humans to humans human carcinogen of association Limited human, sufficient animal, Carcinogenic Carcinogenic Known to be Limited/suggestive strong evidence in exposed humans to humans to humans human carcinogen evidence of that agent acts through relevant association mechanism of carcinogenicity Limited human, sufficient animal Probably Likely to be Reasonably Limited/suggestive carcinogenic carcinogenic expected to be evidence of to humans to humans human carcinogen association Inadequate human, sufficient Probably Likely to be Reasonably Inadequate/ animal, strong evidence that carcinogenic carcinogenic expected to be insufficient evidence carcinogenesis is mediated by to humans to humans human carcinogen to determine whether a mechanism that also operates association exists in humans Inadequate human, limited animal, Possibly Likely to be Reasonably Inadequate/ strong supporting evidence from carcinogenic carcinogenic expected to be insufficient evidence other relevant data to humans to humans human carcinogen to determine whether association exists (Continued)
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From page 136... ...
TABLE 5-2 Continued 136 Type of Evidence IARC EPA NTP IOM Inadequate human, Possibly Likely to be Reasonably Inadequate/ sufficient animal carcinogenic to carcinogenic expected to be insufficient humans to humans human carcinogen evidence to determine whether association exists Limited human, limited Possibly Suggestive evidence Reasonably Limited/suggestive or inadequate animal carcinogenic to of carcinogenicity expected to be evidence of humans potential human carcinogen association Inadequate human, Not classifiable as Suggestive evidence (No statement) Inadequate/ limited animal to carcinogenicity of carcinogenicity insufficient in humans potential evidence to determine whether association exists Inadequate human, inadequate Not classifiable as Inadequate Reasonably Inadequate/ animal, convincing relevant to carcinogenicity evidence to assess expected to be insufficient information that the agent acts to humans carcinogenic human carcinogen evidence to through mechanisms indicating it potential determine whether would likely cause cancer in humans association exists Sufficient animal, strong evidence Not classifiable as Inadequate (No statement)
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From page 137... ...
Evidence suggesting lack of Probably not Not likely to be (No statement) Inadequate/ carcinogenicity in humans and carcinogenic carcinogenic insufficient evidence experimental animals or evidence in humans in humans to determine whether suggesting lack of carcinogenicity association exists in experimental animals consistently and strongly supported by broad range of other relevant data Sources: IARC 1999; IOM 2004; EPA 2005a; NTP 2005.
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From page 138... ...
IARC (2005b) , however, is now considering modifying its rules of evidence so that "possible carcinogenicity can be assessed solely on the basis of strong evidence from mechanistic and other relevant data." Current NTP guidance indicates that an agent can be classified as reasonably expected to be a human carcinogen when there is "convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans" (NTP 2005)
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. In practice, few assessments quantitatively characterize human variability in cancer risk.
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COMMITTEE OBSERVATIONS CONCERNING TOXICITY DATA AVAILABLE FOR RISK ASSESSMENT Guidelines for assessing hazards and dose-response relationships from toxicologic and epidemiologic data have coevolved with scientific developments and laboratory capabilities. In some respects, the human and animal data being generated as described in Chapters 2 and 3 mesh well with the evidence requirements.
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From page 141... ...
Under EPA and IARC carcinogen guidelines, direct evidence of cancer in animals or humans is required if a chemical is to be identified as having carcinogenic potential. In practice, when such data are not available, the chemical is classified as having, for example, "inadequate information to assess carcinogenic potential"; cancer risk is not estimated; and the chemical is generally treated as posing zero cancer risk.
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From page 142... ...
The issue of indirect, systemic toxicity resulting from high-dose testing and the challenges it poses for interpreting findings of cancer, reproductive toxicity, developmental toxicity, and neurotoxicity is discussed in risk-assessment guidelines for these end points. For example, neurotoxicity testing currently relies on apical tests that have a strong emphasis on behavioral end points that can be confounded by other systemic toxicity, such as can be seen at or above the maximum tolerated dose or indicated by moderate maternal toxicity.
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From page 143... ...
Data and Framework for Nondefault Assessment For most environmental agents of concern, the initial default assessment of risk involves extrapolation of findings from studies in very small homogeneous animal populations that are exposed for a portion of their lifespan at doses typically considerably higher than environmental levels to large heterogeneous human populations. The extrapolations have the potential to overestimate or underestimate risk; when the difference between expected human exposure and effect level is relatively small or the costs of indicated exposure reductions are high, additional study may be undertaken either by regulatory authorities or by affected industries.
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From page 144... ...
Guidance is also limited or nonexistent for developing other information useful for nondefault analyses, including data for models for assessing human variability, age dependence, site concordance, and high- to low-dose and cross-species differences in pharmacokinetics. Optimizing further testing to improve the initial characterization of a particular chemical or class of chemicals can be highly contextdependent.
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Developmental Neurotoxicity Study.
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1994. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health Based Exposure Limits.
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National Toxicology Program, Research Triangle Park, NC [online]
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1998. Human variability and noncancer risk assessment -- an analysis of the default uncertainty factor.
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