A multidisciplinary approach to toxicological screening: I. Systemic toxicity.
The toxicity of 10 chemicals, including pesticides (carbaryl, chlordane, heptachlor, and triadimefon), solvents (carbon tetrachloride, dichloromethane, tetrachloroethylene, and trichloroethylene), and industrial chemicals [diethylhexylphthalate (DEHP) and phenol] was examined in the liver, kidneys, spleen, thymus, and adrenals of female F344 rats after 1 or 14 d of oral dosing. For each chemical, 4 doses were based on fractions of the acute LD50, which was estimated using an abbreviated (up-and-down) method. A multivariate analysis (MANOVA) was conducted for each organ using selected measures of toxicity. A post hoc contrast analysis was also conducted for significant MANOVA results in order to determine effective and ineffective doses. A single dose of heptachlor resulted in necrotic lymphocytes in the spleen and thymus at doses > or = 23 mg/kg. Triadimefon altered liver and spleen weights; this effect has not been described previously. Dichloromethane (> or = 337 mg/kg/d for 14 d) increased the incidence of necrosis of individual centrilobular hepatocytes. Trichloroethylene-induced hepatotoxicity was obtained at doses an order of magnitude lower than those reported in the literature. Acute DEHP (150 mg/kg) increased mitotic figures in hepatocytes, which were replaced by hepatocellular cytomegaly after 14 d of dosing at the same level. Following phenol exposure, there was an increased incidence in hepatocellular necrosis at 1 d, and an increased incidence of kidney lesions at 1 and 14 d; these findings were considered to be the result of vascular stasis. Overall, the algorithm used to select doses was effective for both 1- or 14-d dosing regimens. For all chemicals except carbon tetrachloride, the lowest effective dose for systemic toxicity was within the range of 3-56% of the LD50 for acute dosing, and 1-30% of the LD50 for repeated administration.
Berman
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E
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Schlicht
M
M
Moser
V C
VC
MacPhail
R C
RC
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007668:Kidney / Q000187:drug effects; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D015999:Multivariate Analysis; D010575:Pesticides / Q000633:toxicity*; D010636:Phenols / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000187:drug effects
D010575:Pesticides; D010636:Phenols; D012997:Solvents; D004051:Diethylhexyl Phthalate