Effect of bromine and chlorine positioning in the induction of renal and testicular toxicity by halogenated propanes.
A series of halogenated propanes were studied for renal and testicular necrogenic effects in the rat and correlated to their ability to induce in vivo renal and testicular DNA damage and in vitro testicular DNA damage. 1,2-Dibromo-3-chloropropane (DBCP) and 1,2,3-tribromopropane were most potent in causing organ damage in both kidney and testes. Extensive necrosis was evident at 85 mumol/kg in kidney and at 170 mumol/kg in testis. The dibromomonochlorinated analogue 1,3-dibromo-2-chloropropane was less organ toxic than DBCP and 1,2,3-tribromopropane, but induced more organ damage than the dichloromonobrominated analogues 1-bromo-2,3-dichloropropane and 1,3-dichloro-2-bromopropane. Dihalogenated propanes were even less necrogenic. These observed differences in toxic potency between the halogenated propanes could not be explained by relative differences in tissue concentrations. The ability of the halogenated propanes to induce DNA damage in vivo correlated well with their ability to induce organ damage. However, DNA damage occurred at lower doses and at a shorter period of exposure than organ necrosis. This indicates that DNA damage might be an initial event in the development of organ necrosis by halogenated propanes in general. Further, testicular DNA damage induced by the halogenated propanes in vivo correlated well with the DNA damage observed in isolated testicular cells in vitro, showing that toxicity was due to in situ activation. The numbers, positions, and the types of halogen substituents appear to be important determinants in causing DNA damage and necrogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Låg
M
M
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Omichinski
J G
JG
Brunborg
G
G
Holme
J A
JA
Dahl
J E
JE
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D003404:Creatinine / Q000097:blood; D004249:DNA Damage; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D011407:Propane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013733:Testicular Diseases / Q000139:chemically induced* / Q000473:pathology; D014018:Tissue Distribution; D014508:Urea / Q000097:blood
D006846:Hydrocarbons, Halogenated; D014508:Urea; C007318:1,2-dibromo-3-chloropropane; D003404:Creatinine; D011407:Propane