1,2-Dibromo-3-chloropropane (DBCP)-induced toxicity was studied in rat germ cells from different stages of spermatogenesis, separated by centrifugal elutriation, and in Sertoli cells prepared from sexually mature and immature animals. The in vitro metabolic activation of 50 to 250 microM DBCP, measured as covalent binding of 14C-DBCP to macromolecules, was highest in round spermatids, lowest in Sertoli cells and elongating/elongated spermatids, and intermediate in spermatocytes. High concentrations of DBCP (> or = 250 microM) caused a decrease in oxygen consumption and mitochondrial rhodamine 123 uptake, indicating an effect on mitochondrial function. Altered Sertoli cell function, measured as detachment of germ cells in Sertoli-germ cell cocultures, was evident at DBCP concentrations > or = 300 microM. DBCP-induced DNA damage occurred at much lower concentrations (10 to 30 microM) when compared to effects on mitochondrial function and Sertoli cell function. The extent of single strand DNA breaks and alkali-labile sites (ssDNA breaks) measured by the alkaline filter elution technique and the single cell gel electrophoresis assay, were greatest in the round spermatids > spermatocytes = Sertoli cells > elongating/elongated spermatids. The study demonstrates that various testicular cell types show differences in their rates of activation of DBCP to metabolites that bind to macromolecules. DNA is a more sensitive intracellular target in DBCP-induced testicular toxicity than mitochondria. Round spermatids appear to be more susceptible to DBCP-induced ssDNA breaks than spermatocytes, elongating/elongated spermatids, or Sertoli cells.

Animals↗

PubMedDate not supplied

DNA strand breaks in testicular cells from humans and rats following in vitro exposure to 1,2-dibromo-3-chloropropane (DBCP).

Preparations of testicular cells from human organ transplant donors and from Wistar rats were compared with respect to their composition of the different testicular cell types, their ability to metabolize 1,2-dibromo-3-chloropropane (DBCP), and their relative sensitivity to induction of DNA single strand breaks and alkali labile sites (ssDNA breaks) after treatment with DBCP, 4-nitroquinoline N-oxide (4-NQO), and X rays. Flow cytometric and microscopic analysis demonstrated that the interindividual variation in the composition of testicular cell types was considerably greater in the human tissue than in that from rats. The in vitro metabolic activation of DBCP (50 to 250 microM), measured as radiolabel covalently bound to macromolecules, was three-fold faster in rat testicular cells compared to human testicular cells. X rays (1 to 10 Gy) and 4-NQO (0.5 to 2.5 microM) induced ssDNA breaks to a similar extent in both human and rat testicular cells as measured by single cell get electrophoresis (SCGE) and alkaline filter elution. In contrast, 1,2-dibromo-3-chloropropane (DBCP) (3 to 300 microM) caused no significant DNA damage in human testicular cells, whereas in rats there was a clear concentration-dependent increase in ssDNA breaks. The data show that, compared to rats, testicular cells from humans are less efficient in activating DBCP to metabolites binding covalently to macromolecules. However, from the rate of covalent binding observed one would expect a significant degree of DBCP-induced ssDNA breaks in the human testicular cells. The low level of DBCP-induced ssDNA breaks in human testicular cells could indicate that different reactive DBCP metabolites are involved in binding to cellular macromolecules compared to DNA damage, or that different rates of DNA repair exist in human and rat testicular cells.

4-Nitroquinoline-1-oxide↗

PubMedDate not supplied

Species differences in kidney toxicity and metabolic activation of tris(2,3-dibromopropyl)phosphate.

Explore the source record for details and available documents.

Animals↗

PubMedDate not supplied

Hazard characterisation of chemicals in food and diet. dose response, mechanisms and extrapolation issues.

Hazard characterisation of low molecular weight chemicals in food and diet generally use a no-observed-adverse-effect level (NOAEL) or a benchmark dose as the starting point. For hazards that are considered not to have thresholds for their mode of action, low-dose extrapolation and other modelling approaches may be applied. The default position is that rodents are good models for humans. However, some chemicals cause species-specific toxicity syndromes. Information on quantitative species differences is used to modify the default uncertainty factors applied to extrapolate from experimental animals to humans. A central theme for extrapolation is unravelling the mode of action for the critical effects observed. Food can be considered as an extremely complex and variable chemical mixture. Interactions among low molecular weight chemicals are expected to be rare given that the exposure levels generally are far below their NOAELs. Hazard characterisation of micronutrients must consider that adverse effects may arise from intakes that are too low (deficiency) as well as too high (toxicity). Interactions between different nutrients may complicate such hazard characterisations. The principle of substantial equivalence can be applied to guide the hazard identification and hazard characterisation of macronutrients and whole foods. Macronutrients and whole foods must be evaluated on a case-by-case basis and cannot follow a routine assessment protocol.

Animals↗

PubMedDate not supplied

A comparative study of chemically induced DNA damage in isolated human and rat testicular cells.

Testicular cells prepared from human organ transplant donors or from Wistar rats were used to compare 15 known reproductive toxicants with respect to their ability to induce DNA damage, measured as single-strand DNA breaks and alkali labile sites (ssDNA breaks) with alkaline filter elution. The compounds tested included various categories of chemicals (i.e., pesticides, industrial chemicals, cytostatics, and mycotoxins) most of which are directly acting genotoxicants (i.e., reacting with DNA either spontaneously or via metabolic activation). In addition, a few indirect genotoxic and nongenotoxic reproductive toxicants were included. Six of the chemicals induced no significant levels of ssDNA breaks in human and rat testicular cells; methoxychlor (10 to 100 microM, human and rat), benomyl (10 to 100 microM, human and rat), thiotepa (10 to 1000 microM, human and rat), cisplatin (30 to 1000 microM, human; 100 to 1000 microM, rat), Cd2+ (30 to 1000 microM, human; 100 to 1000 microM, rat), and acrylonitrile (30 to 1000 microM, human; 30 to 300 microM, rat). Four chemicals induced significant levels of ssDNA breaks in testicular cells from both species: styrene oxide (> or = 100 microM, rat and human), 1,2-dibromoethane (EDB) (> or = 100 microM, rat; 1000 microM human), thiram (> or = 30 microM, rat; > or = 100 microM, human), and chlordecone (300 microM, rat; > or = 300 microM, human). Finally, five chemicals induced ssDNA breaks in one of the two species. Four chemicals induced significant ssDNA breaks in rat testicular cells only: 1,2-dibromo-3-chloropropane (DBCP) (> or = 10 microM), 1,3-dinitrobenzene (1,3-DNB) (> or = 300 microM), Cr6+ (1000 microM), and aflatoxin B1 (> or = 100 microM), the last two of these produced only a minor positive response. One chemical, acrylamide, induced a marginal increase in ssDNA breaks in human at 1000 microM, but not in rat testicular cells. Although based on a limited number of donors, the data indicate a close correlation between the induction of DNA damage in human and rat testicular cells in vitro. For some chemicals, however, there appears to be differences in the susceptibility to chemically induced ssDNA breaks of isolated testicular cells from the two species. The data indicate that the parallel use of human and rat testicular cells provides a valuable tool in the assessment of human testicular toxicity.

Adult↗

PubMedDate not supplied

Metabolic activation of 1,2-dibromo-3-chloropropane to mutagenic metabolites: detection and mechanism of formation of (Z)- and (E)-2-chloro-3-(bromomethyl)oxirane.

1,2-Dibromo-3-chloropropane (DBCP), a haloalkane nematocide and soil fumigant, is metabolically activated to chemically reactive species that are direct-acting mutagens in a Salmonella typhimurium TA 100 test system. Studies in vitro with rat liver microsomes indicated that oxidation at carbon 3 resulted in the formation of an unstable gem-chlorohydrin that rearranged with elimination of hydrogen bromide to form (Z)-2-chloro-3-(bromomethyl)oxirane [(Z)-CBPO] and (E)-2-chloro-3-(bromomethyl)oxirane [(E)-CBPO]. Gas chromatography-mass spectrometry (GC-MS) with positive ion chemical ionization (CI) was employed to identify (Z)-CBPO and (E)-CBPO by comparison of characteristic fragment ions in their CI mass spectra with those observed for authentic standards. Quantitative GC-MS methodology was exploited to quantitate the rate of formation of (Z)-CBPO and (E)-CBPO from DBCP and analogues of DBCP specifically deuterated at carbon 1 and carbon 3. The rate of formation of Z- and E-isomers of CBPO was 31 and 33 pmol/(min.mg of protein), respectively, from DBCP; substitution with deuterium at carbon 1 increased the rate of epoxide formation by 50%, whereas CBPO formation could not be detected from a substrate labeled with deuterium at carbon 3. Both epoxides were directly acting mutagens to S. typhimurium TA 100. (Z)-CBPO caused approximately twice as many his+ revertants/nmol compared to (E)-CBPO. Oxidation at carbon 2 of DBCP resulted in the formation of a bifunctional alkylating agent, 1-bromo-3-chloroacetone, presumably via the intermediacy of an unstable gem-bromohydrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antinematodal Agents↗

PubMedDate not supplied

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)

Animals↗

PubMedDate not supplied

Organ and species differences in microsomal activation of methyldopa.

The covalent binding of 3H-methyldopa to microsomal protein in the presence of NADHP and oxygen was studied in various microsomal preparations. Rat and mouse liver microsomes showed high binding, hamster and guinea pig liver microsomes gave intermediate values, whereas no binding was seen with rabbit liver microsomes. No activation of methyldopa was detected with kidney microsomes. Lung microsomes from rats, guinea pigs, and rabbits were quite active with respect to methyldopa binding, and the reactions were totally blocked by superoxide dismutase. There was no sex difference in the binding of methyldopa in liver microsomes from adult rats. No methyldopa activation could be detected in fetal liver microsomes, whereas a rapid increase in activity to above adult levels occurred during the first 2 days after birth.

Aging↗