REGULATORY

TOXICOLOGY

AND

PHARMACOLOGY

16, 109- 110 ( 1992)

EDITORIAL Mechanistic

Data in Scientific Public Health Decisions

When national policies for assessing human risk from exposure to chemicals that cause cancer in experimental animals are relaxed based on mechanistic data, all data pertinent to a particular issue or mechanism must be evaluated objectively for consistency and completeness. Differences of opinion on the strength of evidence supporting hypotheses are healthy and essential in science, especially if they lead to improved scientifically based public health decisions. Scientific advancement is based on the principle of hypothesis testing, and public health policies require more than a dependence on presumptions and working hypotheses from limited research. If alternative hypotheses are plausible using the same data, then these too must be examined thoroughly for potential validity, especially when public health status is involved. A case in point is illustrated in this issue, in which an alternative interpretation of the existing data on the cu2uglobulin model of kidney carcinogenesis is reported. Similar controversies exist in other topics of chemical carcinogenicity, including the relevance of effects observed at the maximum tolerated dose, roles of cell proliferation and chemical-induced toxicity, existence of threshold responses for carcinogens that act via receptor-mediated processes, interpretation of studies showing increases in mouse liver tumors, and the use of pharmacokinetic data to decipher pathways and mechanisms of carcinogenesis. Some contend that humans are not at incremental risk of developing kidney cancer from exposure to certain simple organic compounds of low reactivity that induce a2uglobulin (protein droplet) nephropathy in male rats. The rationale for this view is based on empirical correlations between the accumulation of this protein and the development of renal tumors in rats exposed to these chemicals and because humans have not been shown to synthesize a2uglobulin. Renal tumors associated with chemicals that induce the cY2uglobulin nephropathy syndrome in rats are thought to result from secondary mechanisms that do not operate in species that lack a2uglobulin. In response to the reported findings on a2u-globulin nephropathy and associated renal carcinogenesis in male rats, and the explanations concerning their potential human relevance, the U.S. Environmental Protection Agency has adopted the view that kidney tumors observed in male rats in conjunction with cY2uglobulin accumulation are not applicable to human risk assessment. In the critical review article in this volume, data gaps and inconsistencies in the current hypothesis linking a2uglobulinassociated nephropathy with renal carcinogenesis are highlighted. According to the present hypothesis, the chemical or metabolite binds to cu2uglobulin leading to accumulation of this protein in renal tubular epithelial cells and subsequent cell death. Regenerative cell proliferation in the affected tubules 109 0213-2300192

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EDITORIAL

presumably leads to the development of renal tumors. Scientific questions raised in this review may lead to the conclusion that the available studies show a possible association, yet are not convincing of the mechanism involved. An alternative hypothesis involving a chemically induced toxic effect in the kidney, mediated by low molecular weight carrier proteins, is proposed as a plausible interpretation of the available published data. This review reveals a number of uncertainties and discrepancies in the current hypothesis on the relationship between cu2u-globulin-associated nephropathy and renal carcinogenesis that need to be resolved, including: (a) the site or sites of interaction between a2u-globulin and the bound chemical or metabolite, (b) the role of unbound chemical or metabolite in the kidney, (c) the relationship between binding affinity to a2u-globulin and dose responses for induction of a2u-globulin-associated nephropathy, (d) the significance of a2u-globulin accumulation in the kidney, (e) the in vivo relevance of in vitro data, (f) results of studies showing a2u-globulin-associated nephropathy without increases in the incidence of renal tumors, (g) the correlation between a2uglobulin nephropathy and carcinogenicity in rats and liver carcinogenicity in mice, and (h) the possibility that these chemicals induce tumors at other sites in humans. Because data on sustained cell proliferation have been reported for only two chemicals that induced a2u-globulin-associated nephropathy and renal tumors in longterm studies (unleaded gasoline and d-limonene), it is obvious that a broader database on dose-response relationships between sustained tubular cell necrosis, cell proliferation, and renal carcinogenesis is needed. Likewise, there is need for further research to understand the basis for increased cell proliferation in renal tubules and the mechanistic relationship between cell proliferation and renal carcinogenesis. The view that cell division is the limiting factor in kidney cancer (or any cancer) is speculative and should be recognized as such. Finally, are there proteins in humans that serve a role similar to that of a2u-globulin in male rats? Hopefully the alternative hypothesis review paper will serve to stimulate further work and scientific debate to clarify uncertainties and thus strengthen our understanding of the mechanisms involved in chemical carcinogenesis. This then will provide a sounder scientific basis for determining the potential human risk, or lack thereof, from occupational and environmental exposure to these chemicals. RONALD L. MELNICK

Division of Biometry and Risk Assessment National Institute of Environmental Health Sciences P.O. Box 12233, Research Triangle Park, North Carolina 27709

Mechanistic data in scientific public health decisions.

REGULATORY TOXICOLOGY AND PHARMACOLOGY 16, 109- 110 ( 1992) EDITORIAL Mechanistic Data in Scientific Public Health Decisions When national poli...
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