A multidisciplinary approach to toxicological screening: I. Systemic toxicity

J Toxicol Environ Health. 1995 Jun;45(2):127-43. doi: 10.1080/15287399509531986.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Adrenal Glands / drug effects
  • Algorithms
  • Animals
  • Diethylhexyl Phthalate / administration & dosage
  • Diethylhexyl Phthalate / toxicity*
  • Female
  • Kidney / drug effects
  • Lethal Dose 50
  • Liver / drug effects
  • Multivariate Analysis
  • Pesticides / toxicity*
  • Phenols / administration & dosage
  • Phenols / toxicity*
  • Rats
  • Rats, Inbred F344
  • Solvents / administration & dosage
  • Solvents / toxicity*
  • Spleen / drug effects
  • Structure-Activity Relationship
  • Thymus Gland / drug effects

Substances

  • Pesticides
  • Phenols
  • Solvents
  • Diethylhexyl Phthalate