title: The liver, kidney, and thyroid toxicity of chlorinated benzenes.
abstract: The acute toxicity of a number of chlorinated benzenes, ranging from monosubstituted to pentasubstituted benzenes, was studied in rats. Toxic effects on the liver, the kidneys, and the thyroid were monitored after a single ip administration of 1, 2, or 4 mmol/kg monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2-DICB), 1,4-dichlorobenzene (1,4-DICB), 1,2,4-trichlorobenzene (1,2,4-TRCB), and pentachlorobenzene (PECB). Due to its low solubility, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TECB) was tested at a highest dose of 0.8 mmol/kg. 1,2-DICB and 1,2,4-TRCB produced the most severe hepatotoxic effects when compared with an equimolar dose of the other chlorinated benzenes, as determined by plasma ALT profile and histopathological changes after 72 hr. MCB was considerably less hepatotoxic. Severe degenerative damage to the kidney was only observed in a few rats treated with 1,2,4-TRCB. However, protein droplets in the tubular epithelial cells were observed at 72 hr after administration of 1,4-DICB, 1,2,4-TRCB, 1,2,4,5-TECB, and PECB. In the latter two groups, these protein droplets were still observed 9 days after administration. All chlorinated benzenes tested excluding MCB induced a reduction in plasma thyroxine levels. The extent of decrease in plasma thyroxine was more severe in rats treated with 1,2,4-TRCB or PECB and correlated well with the relative binding affinities of the phenolic metabolites to the plasma transport protein for thyroxine, i.e., transthyretin. The present study indicates that the establishment of a structure-activity relationship with regard to toxicity depends on the sensitivity of the respective target organs. In the series of (poly)chlorinated benzenes studied, ranging from mono- to pentachlorobenzene, the most severe effects on liver, kidney, and thyroid were observed for 1,2,4-substitution.
authors.affiliation: Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: den Besten
authors.forename: J J
authors.initials: JJ
authors.lastname: Vet
authors.forename: H T
authors.initials: HT
authors.lastname: Besselink
authors.forename: G S
authors.initials: GS
authors.lastname: Kiel
authors.forename: B J
authors.initials: BJ
authors.lastname: van Berkel
authors.forename: R
authors.initials: R
authors.lastname: Beems
authors.forename: P J
authors.initials: PJ
authors.lastname: van Bladeren
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002722:Chlorobenzenes / Q000009:adverse effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011228:Prealbumin / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D002722:Chlorobenzenes; D011228:Prealbumin; D013963:Thyroid Hormones; D000410:Alanine Transaminase; D005978:Glutathione