Thursday, December 01, 2005

Site Concordance Between Laboratory and Human Studies is Not Expected - Benzene

There's a historical and a systematic lesson in this bioassay of benzene in rats and mice.
First , historically, a problem with the first attempt to set an OSHA standard for benzene was a lack of a laboratory test showing carcinogenicity. This is not unlike the early history of tobacco toxicology, where there was human data but no laboratory confirmation of carcinogenicity. A lot more happened in the battle over that benzene rule, but one difference between the first and second try was the bioassay reported below.

The epidemiological evidence for benzene is considerably stronger now than the second try at the rule, leading to a 1 ppm limit. The 1 ppm limit leaves behind very large cancer risks, even though it's the lowest PEL in the world.

Second issue is site concordance. If an agent causes tumors at one site in the laboratory, and a study in people shows an excess at a different site, what's up with that for risk assessment? Some site concordance is trivial, for example, silica dust and the lung; point of contact. The prominence of liver tumors in oral dosing bioassays is also possibly trivial, since the first major capillary bed and metabolic site for ingested stuff is the liver.

Although benzene caused non cancer damage to the hematopoeitic system, the tumors observed in both mice and rats were oral skin tumors and salivary gland tumors. This demonstrates that for one of the best known human carcinogens, the human tumor sites and laboratory tumor sites are not necessarily the same. This was an oral bioassay; many volatile organics cause lung tumors in mice by inhalation.

A positive bioassay at any site provides biological plausibility to an epidemiological association at any site in people.

Environ Health Perspect. 1989 Jul;82:125-63.

Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Huff JE, Haseman JK, DeMarini DM, Eustis S, Maronpot RR, Peters AC, Persing RL, Chrisp CE, Jacobs AC.

National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.

Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3F1 mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals. For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3F1 mice, and female B6C3F1 mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity

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