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Response to Comment on “Relative Susceptibility of Animals and Humans to the Cancer Hazard Posed by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Using Internal Measures of Dose” SIR: We appreciate the opportunity to respond to the comments of Dankovic and Stayner regarding our paper (1). To a large degree, they raise issues which indicate that they misinterpreted the goal of our analysis. For example, they recommend use of allometric scaling in order to normalize animal and human responses. However, in the case of TCDD, responses and sensitivity of different species vary widely, and the differences in response are not related to allometric parameters (for example, hamsters are more than 1000 times less sensitive to the acute toxicity of TCDD than guinea pigs). In light of the wide interspecies variability in sensitivity and response, our goal was not to “normalize” the rat and human responses, but rather, to examine and compare the doseresponse data available in humans and rats for TCDD, using dose measures that should be biologically relevant, in order to evaluate their relative sensitivity. As we concluded in our paper, if the human cancer responses in the NIOSH cohort are due to TCDD (and there is debate regarding this issue), then regardless of the dose metric chosen, humans are not responding to the same degree as the rats. Dankovic and Stayner acknowledge that AUC (area-underthe-curve) has been shown to be relevant to extrapolating cancer potency of alkylating agents, but assert that it would be “unlikely” to apply to TCDD because of the different mechanism of action of TCDD. However, the pharmacokinetic characteristics of TCDD (highly persistent) and its mechanism of action (that is, as a receptor mediated promoter) argue strongly for an AUC-based dose metric. For example, the classical definition of a tumor promoter requires that the promoter be present at a sufficient concentration in a tissue for a minimum (usually quite long) period of time before a response will be observed (2). In short, although we acknowledge that it has not been used frequently in the past, and our analysis does not establish which dose metric is most appropriate, we believe that due to TCDD's persistence in biological organisms, its interaction with the Ah receptor and its classification as a promoter, some form of AUC is intuitively likely to be a superior measure compared to daily dose. Dankovic and Stayner argue that lifetime average concentration is the best dose metric for comparing the rat and human dose-responses, and we infer that they are referring to our AUC-based calculation of lifetime average concentration. Although it is possible that this is the best dose metric, further work would be required for us to embrace this approach. The potential difficulty in using lifetime average concentration is that the exposure profiles of occupationally exposed human populations and experimental animal studies are quite different. As our paper illustrated, rats experienced steady-state tissue levels for a substantial portion of their lifetime. In contrast, the human serum TCDD concentration vs time curve requires 40 years to reach steady state, and in practice, steady state was never reached by any of the occupational cohort. We suggest that interspecies comparisons or comparisons between an occupationally exposed cohort and the general population with a steady-state background level, based on a single average concentration, S0013-936X(97)02010-5 CCC: $15.00 Published on Web 01/01/1998
1998 American Chemical Society
are likely to be misleading. Use of AUC or an AUC-based dose metric (perhaps accounting for metabolic rate differences) allows these differences in exposure characteristics to be taken into account. We discussed issues related to differences in lifetime between humans and animals and possible scaling approaches in our paper, and acknowledge that more work remains to be done on this issue. Dankovic and Stayner make the points that (a) the risk estimates for humans and rats are not significantly different in the low dose range, (b) rats experience lower excess risk than humans for serum TCDD concentrations less than 800 ppt, and (c) “since typical background levels of TCDD in the U.S. population are on the order of 2-9 ppt, one could reasonably conclude that excess risk estimates based on the rat might actually underestimate the human response for exposures of environmental concern”. In fact, neither the animal nor the human data support the existence of any increase in cancer risk at low TCDD exposure levels. Rodents exposed to low doses experienced decreases in tumors (3) (decreases that are mirrored in the two-stage rat liver model (4) and which may well be true decreases due to hormesis). The group of NIOSH workers employed for less than 1 year had an SMR of 96, despite a mean lifetime average serum TCDD level 12-55 times higher than the national average serum TCDD levels. The interpretation of these data to suggest a cancer risk at low level exposure is an artifact of the regulatory approach to cancer risk extrapolation. Specifically, chemicals like TCDD that are shown to produce a decrease in tumors at low doses, with tumor increases observed only at much higher doses, are assumed to pose a plausible cancer hazard at all doses. The actual animal and human data provide no support for the contention that the animal data may underestimate human cancer risk, since neither the animal nor the human data indicate a cancer risk at low doses. Dankovic and Stayner correctly observe that body weight scaling and other allometric procedures have been historically used for interspecies scaling. These may be appropriate when nothing is known about the chemical- and species-specific pharmacokinetics and pharmacodynamics and only “external” doses are known. However, the scientific support for such procedures is not sufficient to justify ignoring more detailed knowledge of comparative pharmacokinetics. In particular, the papers on interspecies comparisons cited by Dankovic and Stayner provide no support for using a daily dose metric for the family of persistent organics which have long biologic half-life and minimal genotoxic activity. Numerous studies have shown that TCDD pharmacokinetics can not be predicted nor extrapolated on the basis of these simplistic measures (5). We continue to believe that, given the wealth of data on the carcinogenic action and pharmacokinetics of TCDD in both animals and humans, more sophisticated risk evaluations and estimates can be made than those based on default extrapolation procedures using the experimental rat data. We are pleased that our paper has stimulated debate regarding selection of dose metrics. At a recent symposia on dose metrics sponsored by the International Life Science Institute and Resources for the Future (6), a majority of the views expressed supported the relevance of AUC-based dose metrics (in particular, AUC above a specific concentration) to evaluate and predict adverse effects of TCDD and related persistent organic compounds. AUC as a dose measure is being used and evaluated in analyses of a variety of chemicals and responses (7, 8). In our view, improvements in our understanding of how to properly characterize dose and to VOL. 32, NO. 4, 1998 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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quantitatively adjust for differences among species for the diversity of chemicals to which persons are exposed will be one of the more important advances in toxicology (and the resulting impact on environmental regulation) in the coming decade.
Literature Cited (1) Aylward, L. L.; Hays, S. M.; Karch, N. J.; Paustenbach, D. J. Environ. Sci. Tech. 1996, 30, 3534-3543. (2) Pitot, H. C. Fundamentals of Oncology, 3rd ed.; Marcel Dekker: New York, 1986. (3) Kociba, R. J.; Keyes, D. G.; Beyer, J. E.; Carreon, R. M.; Wade, C. E.; Dittenber, D. A.; Kalnins, R. P.; Frauson, L. E.; Park, C. N.; Barnard, S. D.; Hummel, R. A.; Humiston, C. G. Toxicol. Appl. Pharmacol. 1978, 46, 279-303. (4) Pitot, H. C.; Goldsworthy, T. L.; Moran, S.; Kennan, W.; Glauert, H. P.; Maronpot, R. R.; Campbell, H. A. Carcinogenesis 1987, 8, 1491-1499. (5) Lawrence, G. S.; Gobas, F. A. P. C. Chemosphere 1997, 35, 427452. (6) Dosimetry for Persistent Chemicals Symposium; International Life Sciences Institute and Resources for the Future: Washington, DC, April 17, 1997. (7) Storm, J. E.; Rozman, K. K. Evaluation of alternative models for establishing safe levels of occupational exposure to vinyl halides. Reg. Toxicol. Pharmacol. 1997, 25, 240-255.
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(8) Tzimas, G.; Thiel, R.; Chahoud, I.; Nau, H. Toxicol. Appl. Pharmacol. 1997, 143, 436-444.
Lesa L. Aylward* and Nathan J. Karch Karch & Associates, Inc. 1701 K Street, N. W., Suite 1000 Washington, DC 20006 (202) 463-0400
Sean M. Hays ChemRisksA Division of McLaren/Hart 5900 Landerbrook Drive, Suite 100 Cleveland, Ohio 44124
Dennis J. Paustenbach ChemRisksA Division of McLaren/Hart 1135 Atlantic Avenue Alameda, California 94501 ES972010E
