Chronic bioassays

Gold LS, Manley NB, Slone TH et al (2001) Compendium of chemical carcinogens by target organ results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys. Toxicol Pathol 29 639-652... 

The toxic effects of pesticides can be diverse and depend on the sensitivity of organisms to these toxicants, and the pesticide concentration or bioavailability. Typically, the short- and long-term effects of pesticides have been evaluated through acute or chronic toxicity bioassays, respectively, using lethality endpoints and sublethal endpoints (e.g., growth and reproduction), particularly these last in chronic bioassays. 

Endocrine Effects. Thyroid hyperplasia and pituitary cysts were observed in rats, but not mice, in a chronic bioassay study with endrin administered in the feed (NCI 1978). Treon et al. (1955) found diffuse degeneration of the adrenal glands in rats dosed with >1.25 mg/kg/day in their feed for 2 years however, the adrenal effects were absent at the 0.25 mg/kg/day dose. There has been no evidence of endocrine effects in occupationally exposed human populations. 

Endocrine Effects. Thyroid hyperplasia and pituitary cysts were observed in rats, but not in mice, in a chronic bioassay study with endrin administered in the feed (NCI 1978). There has been no evidence of endocrine effects in occupationally exposed populations. 

No studies were located regarding carcinogenicity of cyanide in humans or animals. The results of the chronic bioassays suggested above may contribute some new insights. 

The carcinogenicity of 1,2-dibromoethane by the oral route has been examined in a chronic bioassay conducted by NCI (1978). The chemical was administered by gavage in corn oil to rats and mice. Because of dose adjustments during the study, doses were expressed as time-weighted average (TWA) as follows high doses for rats were 41 mg/kg/day (males) and 39 mg/kg/day (females) low doses for rats were 38 mg/kg/day (males) and 37 mg/kg/day (females) the high dose for male and female mice was 107 mg/kg/day and the low dose for male and female mice was 62 mg/kg/day. 

Van Duuren BL, Melchionne S, Seidman I, et al. 1986. Chronic bioassays of chlorinated humic acids in B6C3F1 mice. Environ Flealth Perspect 69 109-117. 

A chronic bioassay (one year) in a non-rodent mammalian species (usually the dog). 

Mononuclear Cell Leukemia (MNCL) is unique to the rat, and is only common in the F-344 (common name Fischer rat) inbred rat strain, which is the strain used by the U.S. National Toxicology Program (NTP). Elevated incidences of MNCL have been observed in a number of chronic bioassays in the F-344 rat. The frequency differs between males and females, with an incidence in males around 50%, and an incidence in females around 30%, with a large variation from study to study. It has been shown for some genotoxic carcinogens that exposure does not lead to an increase in MNCL in the F-344 rat, while a number of substances, which are believed to be noncarcinogens,... 

Lijinsky W Chronic bioassay of benzyl chloride in F344 rats and (C57BL/6JxBALB/c) FI mice. J Natl Cancer Inst 76 1231-1236, 1986... 

Van den Heuvel-Greve, M.J., Rostma, R, Jol, J., Kooman, H., Dubbeldam, M., Schipper, C.A. and Kater, B. (2007). A chronic bioassay with the estuarine amphipod Corophium volutator Test method description and confoimding factors. Chemosphere 66 (7) 1301-1309. 

The National Cancer Institute (NCI) concluded that diazinon was not carcinogenic in either rats or mice following chronic bioassays in Fischer 344 rats and B6C3Fj mice (NCI 1979). 

Information on carcinogenic effects of PBDEs in animals is limited to results of chronic bioassays of decaBDE mixtures in rats and mice (Kociba et al. 1975 Norris et al. 1975b NTP 1986). As summarized below, these studies provide limited evidence for the carcinogenicity of decaBDE in animals. No carcinogenicity studies of octaBDE or pentaBDE were located in the available literature. 

Van Duuren. B.L., Melchionne, S. Seidman, I. (1987) Carcinogenicity of acylating agents Chronic bioassays in mice and structure-activity relationships (SARC). J. Am. Coll. Toxicol., 6, 479-487... 

Cancer. No studies were found regarding the carcinogenicity of chlorobenzene in humans. In a chronic bioassay in animals, chlorobenzene (up to 120 mg/kg/day) did not produce increased tumor incidences in mice of both sexes or in female rats (NTP 1985). It was noted, however, that male rats showed a statistically significant increase in neoplastic nodules at the highest dose level tested. While there is strong evidence for neoplastic nodules, existing data are inadequate to characterize the potential for chlorobenzene to cause cancer in humans and animals. 

The results of the chronic bioassays showed somewhat lower survival of high dose male rats (63 mg tin/kg/day as stannous chloride) compared to the controls. The data in mice showed survival of control males was affected more than the dosed groups (82 and 164 mg tin/kg/day), but survival of the female dosed groups was affected less than the controls (NTP 1982). 

Among their multiple uses, acute and chronic bioassays have served, for example, to rank and screen chemicals in terms of their hazardous potential, to undertake biomonitoring studies, to derive water quality criteria for safe release of single chemicals into aquatic bodies and to assess industrial effluent quality in support of compliance and regulatory statutes. 

Martinez-Madrid, M., Rodriguez, P. and Perez-Iglesias, J.I. (1999) Sediment toxicity bioassays for assessment of contaminated sites in the Nervion River (Northern Spain). I. Three-brood sediment chronic bioassay of Daphnia magna Straus, Ecotoxicology 8, 97-109. 

Pereira, A.M.M., Soares, A.M.V.M., Goncalves, F. and Ribeiro, R. (2000) Water-column, sediment, and in situ chronic bioassays with cladocerans, Ecotoxicology and Environmental Safety 47 (1), 27-38. 

Ziehl, T.A. and Schmitt, A. (2000) Sediment quality assessment of flowing waters in South-West Germany using acute and chronic bioassays, Aquatic Ecosystem Health and Management 3 (3), 347-357. 

It now seems possible to go one step further and to include chronic toxicity testing for several species into the environmental protection equation. Chronic bioassays could be utilized in several ways to ... 

Giesy, J.P. and Graney, R.L. (1989) Recent developments in and intercomparisons of acute and chronic bioassays and bioindicators, Hydrobiologia 188/189, 21-60. 

Two-year chronic bioassay was conducted in rats up to 28x human dose (no increase in benign or malignant neoplasms)... 

Two-year rat chronic bioassay in rodents was performed Increased incidence of adrenal medullary hyperplasia and pheochromocytoma observed... 

Gart JJ, Chu KC, Tarone RE (1979) Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. J Natl Cancer Inst 62 957-974... 

In the absence of a chronic bioassay for sulfur mustard, the two approaches described above for estimating an upper limit on the carcinogenic potency give remarkably similar results—1.6 and 5.3 per mg/kg per day for lifetime exposure. Those potency values are less than an order of magnitude lower than the 9.5 per mg/kg per day derived by ORNL (see Table 7-2). That would indicate that the potency estimate of 132 per mg/kg per day relative to BCME (described earlier) is too high... 

Secondary sources report the following oral LDso s in rats 725 mg/kg (RTECS 1988) and 14.1 g/kg (Grayson 1978). Since these values were obtained from secondary sources, no details were available to assess the quality of these data. Survival was poor in both treated and control rats and mice in the chronic bioassay conducted by NCI (1977), but a significant dose-related trend for mortality was noted in the male rats and mice. The deaths could not be attributed to cancer or any other non-neoplastic lesions, though pneumonia was observed in a large percentage of the rats, and this was thought to be related to the increased mortality (NCI 1977). 

The available data in animals suggest that inhaled 1,1-dichloroethane may be nephrotoxic. However, this finding is limited to one species (cat) and was not observed in three other species tested under the same conditions. Another effect observed in animals but not humans following inhalation exposure to 1,1-dichloroethane exposure is fetotoxicity. Suggestive, but inconclusive, evidence of carcinogenicity was obtained in an oral chronic bioassay of 1,1-dichloroethane in rats and mice. 

The database for the health effects of 1,1-dichloroethane in experimental animals is lacking, and the studies reviewed consisted primarily of one subchronic inhalation study, one inhalation developmental toxicity study, and two oral chronic bioassays. No information is available on the effects of 1,1-dichloroethane following dermal exposure. The limited information available in animals suggests that 1,1-dichloroethane may be nephrotoxic, fetotoxic, and possibly carcinogenic. The data also indicate that 1,1-dichloroethane is considerably less toxic than 1,2-dichloroethane and the tetrachlorinated aliphatics. 

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