U.S. Environmental Protection Agency, Office of Pesticide Programs, 1200 Pennsylvania Avenue, N.W., Washington, D.C. 20460
1 To whom correspondence should be addressed. Fax: +1-703-5147; E-mail: dellarco.vicki{at}epamail.epa.gov.
Received February 18, 2004; accepted February 23, 2005
Key Words: cancer risk assessment; carcinogenicity mechanisms; human relevance; doseresponse assessment.
When the United States Environmental Protection Agency (USEPA) published guidelines for carcinogen risk assessment in 1986, it provided essentially no guidance on how to consider mechanistic information. The guidelines simply pointed out that "The Agency will review each assessment as to the evidence on carcinogenesis mechanisms and other biological or statistical evidence that indicates the suitability of a particular extrapolation model." (USEPA, 1986). At that time, mechanisms of carcinogenesis were largely unknown and empirically difficult to approach. Nonetheless, as mechanistic data became available, the Agency considered it in formulating science policies, e.g., alpha2u-globulininduced rat renal tumors (USEPA, 1991
) and thyroid follicular cell rodent tumors and disruption of thyroid homeostasis (USEPA, 1998
) or in chemical-specific assessments, e.g., bladder tumors induced by melamine through formation of urinary calculi (USEPA, 1988
).
In 1996, the Agency formally proposed to make information on the mode of carcinogenic action a pivotal point of the cancer risk assessment process (USEPA, 1996). Because complete knowledge of how an agent causes cancer is unlikely to exist (certainly for the near term), the 1996 guidelines put forth the notion of understanding mode of action versus mechanism of action. The former being a less detailed biochemical description of events than is meant by mechanism of action. The mode of action is sufficient evidence to draw a reasonable working conclusion concerning the agent's influence on key processes. The mode of action concept permits information on precursor events to be evaluated and incorporated into the risk assessment process in a realistic way.
The most frequent comment about the Agency's 1996 proposed revision of its cancer risk assessment guidelines was that more guidance was needed on how to evaluate an agent's mode of action. A few comments raised concern that the new USEPA guidelines would not be public health protective and opposed using mode of action data. In response, in 1999, EPA incorporated a mode of action framework analysis (USEPA, 1999) in conjunction with work by the International Programme for Chemical Safety (IPCS) (Sonich-Mullin et al., 2001
). This framework provided assurance that a rigorous and transparent approach would be taken to using mode of action data in the Agency's cancer risk assessments, and it was well received by the scientific community. The mode of action framework is derived from considerations for causality used in epidemiologic investigations, which were originally articulated by Hill (1965)
. The Hill criteria were later modified by the U.S. Department of Health and Human Services (USHHS, 1982
) and by Faustman et al. (1997)
to extend to experimental animal studies. The publication of the USEPA 1999
framework provided an important tool with which the Agency can promote and formalize the use of mode of action data in cancer assessment.
Mode of action data have come into play in several ways in EPA risk assessments. It has been critical in informing the doseresponse relationship below the experimental observable range of tumors, and thus it is useful in establishing more appropriate guidance levels for environmental contaminants. The Agency's traditional linear default extrapolation procedure for modeling tumor incidence has been a longstanding and often controversial issue. The 1986 USEPA guidelines provided only one doseresponse default, namely the linear extrapolation procedure. The 1999 (and 1996) guidelines advanced this issue by providing two default extrapolation approachesone linear and and one nonlinear. Application of the nonlinear default extrapolation procedure (typically a margin of exposure analysis or determination of a reference dose/concentration) is based on the mode of action understanding about the agent. It was acknowledged in the 1999 (1996) guidelines that "true thresholds" are experimentally difficult to establish. Thus, without requiring the extensive data needed to develop a sophisticated biologically based model, the nonlinear default procedure provided a practical means of incorporating data on the key events integral to the carcinogenic processes that precede the development of tumors, and that contribute to the shape of the overall doseresponse curve.
Since the publication of the 1999 guidelines there have been several examples of departure from the linear extrapolation procedure used to estimate potential human cancer risk. Most notable among them is chloroform, a commonly found drinking water disinfection by-product that has long been a subject of concern for cancer. Experimental evidence demonstrated that chloroform resulted in liver and kidney rodent tumors through a mode of action consistent with a nonlinear biological process, i.e., cytotoxicity followed by regenerative proliferation (USEPA, 2001). Although the key events leading to rodent tumors are plausible in humans, doses that did not cause cytotoxicity are not likely to be a human cancer concern. Thus, the mode of action data on chloroform permitted a more appropriate doseresponse characterization of the potential human cancer risk at environmental exposure levels.
Questions are often raised about the appropriateness of using rodent data in evaluating human cancer risk. Over the years the Agency has seldom departed from the assumption that induced tumors in animals indicate a potential for carcinogenicity in humans. A well-known exception, however, are those agents that result in accumulation of alph2u-globulininduced renal toxicity and neoplasia in male rats. Early experience with the original mode of action framework (Sonich-Mullin et al., 2001; USEPA, 1999
) proved it to be valuable for evaluating how an agent leads to a tumor response in laboratory animals. That experience also showed that the framework needed to be enhanced to provide more guidance concerning how to take that understanding and evaluate the human relevance of the mode of action in animals. Thus, in 2002 the EPA co-sponsored a project with the International Life Sciences Institute Risk Science Institute (ILSI-RSI) to develop a framework to evaluate the human relevance of laboratory animal tumors.
An expert group convened by ILSI-RSI developed the decision logic for understanding the biological events leading to an animal tumor response and how these events relate to humans (Cohen et al., 2004). This human relevance framework was illustrated with several examples. In the case of PPAR agonists, for example, taking into account kinetic and dynamic factors, it was concluded that these rodent liver tumors are not likely to occur in humans (Klaunig et al., 2003
). The IPCS has recently initiated a project to provide a global perspective and internationally harmonize a conceptual approach to determining the human relevance of animal tumors (see: http://www.who.int/ipcs/methods/harmonization/areas/cancer/en/).
The Agency often receives data thought to address the relation between mode of action and human relevance. Such data do not always make a complete and convincing case. Furthermore, such information is not typically presented in a consistent or logical structure. It would be helpful to risk assessors if mode of action information was submitted in a framework structure (Cohen et al., 2004; Sonich-Mullin et al., 2001; USEPA, 1999
), so that facts could be laid out in a logical manner and serve as the basis on which conclusions regarding a postulated mode of action and human relevance can rest. Presentation of mode of action data in a framework structure does not dictate an answer, and evaluation of the assessment may not always lead to the conclusion that a postulated mode of action is supported by the data. Nevertheless, use of the analytical approach provided by a mode of action framework can be very useful to risk assessors who must consider the weight of evidence that supports a proposed mode of action. Application of a mode of action framework to data generated from appropriate studies can also be very informative to risk assessors and researchers who may need to address weaknesses in the data or who plan to design additional studies. The thiamethoxam case study presented by Pastoor et al. (2005
, this issue) using the ILSI-RSI framework is an excellent example of how mode of action data can be organized and presented such that independent risk assessors may easily weigh the evidence and evaluate whether a postulated mode of action is supported by the available data.
NOTES
This paper does not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. The opinions expressed within this paper reflect the views of the authors.
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