Summary and Comments
James E. Klaunig, Ph.D
Professor and Directory of Toxicology
Indiana University School of Medicine
1001 Walnut Street, MRF 003
Indianapolis, IN 46202-5196
The six articles above reflect the response by six groups of scientists reflecting the different perspectives and backgrounds of academia, industry, consulting and government. The authors were posed and asked to respond to three sequential questions.
1. Does the understanding of the mechanisms of toxicity affect how agencies assess risks from exposure to toxic substances?
2. Does the understanding of the mechanisms by which the body adapts (i.e. detoxifies, repairs, etc.) to the effects of exposures to toxic substances effect how regulatory agencies assess risks from exposures to toxic substances.
3. If low doses of toxic substances induce apparently beneficial responses (i.e. enhanced longevity, lower incidence of disease) how does and/or could the agency address this?
These questions concern the timely and important issue of how does or how will the regulatory agencies handle mechanistic data in the assessment of human risk. While not specifically earmarked toward cancer induction, not surprisingly many of the responses used cancer risk assessment in consideration of the topic.
The response to the first question varied. While there was an overall agreement within the six manuscripts on the need to apply mechanistic information to the development of meaningful risk assessment, questions regarding the actual practice of utilizing this information in mode of action and mechanistic approaches was less unified. The linear multi-stage model currently in use by regulatory agencies for cancer risk assessment does not necessarily consider mechanistic information on a compound's toxicity. Its' use as suggested by several of the authors, while protective of public health, was overly conservative in its approach and eventual assessment of risk. Brown, et al noted that the use and interpretation of mechanistic data in the application of risk assessment, many times different agencies come to different conclusions from the same data. As an example, Brown cites the different approach to assessing risk assessment of methyl t-butyl ether (MTBE) in drinking water. The US EPA assumed a non-linear mode of action for the tumor induction produced by MTBA in rodents based for the most part on the lack of genetic toxicity exhibited in short-term bioassays. In contrast, the Office of Environmental Health Hazard Assessment in California chose to use a linear model based on the cancer endpoints. As Brown, et al points out, the difference in the acceptable drinking water ranges using these two different approaches to risk assessment resulted in similar endpoints (20-40 ppb for the USEPA determination and 13ppb for the California OEHHA determination).
This result of a similar risk determination using two different methods however is not always seen. An essential theme for all the manuscripts was the fact that the mode of action and mechanistic data can be obtained and should be incorporated into the risk decision making. Several of the authors point out that there appears to be an inconsistency in the use of mode of action data and in defining which data are acceptable to remove the default linear multi-stage approach from the cancer risk assessment.
In response to the second question, all of the authors recognize the concept of hormesis and how in certain circumstances low exposure doses may result either in enhanced repair, enhanced detoxification, or other potential beneficial effects. In general most of the authors expressed a concern that the regulatory agencies have not been able to address or do not understand how to address the concept of hormesis. This may be due in part to the lack of the understanding of mechanism by which chemicals produce hormesis. In addition, a defining of a hormesis response is difficult if the only chronic information available are high dose level data used for cancer endpoint determinations. While, as Poirier and Dourson note, "the USEPA risk assessment paradigm is compatible with the concept of hormesis" this risk analysis must include consideration and application of information from the low dose portion of the dose response curve. As noted by Teaf, the concept of hormesis is readily acknowledged, however, making practical use of this information has proven more difficult.
In the final question, "If low doses of toxic agents induce apparently beneficial effects, how does or could the regulatory agency address this?" From the articles above, it is apparent that the regulatory agencies at this time do not have mechanisms in place to formally and objectively evaluate and consider the issue of beneficial effects in hormesis in evaluating a compound for toxicity and carcinogenicity. Almost all the authors agree that consideration of beneficial effects of agents should be incorporated into mechanistically based risk analysis. The lack of consideration of beneficial effects of chemicals appears to be a chemical class and agency selective event, since pharmaceuticals provide beneficial effects at low doses and toxic effects at high doses. Other examples including nutrients in food such as selenium should provide regulators with model agents to further redefine their risk to benefit approach in assessing a compound's toxicity