Evaluation of unscheduled DNA synthesis (UDS) and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene

Sherman, James H.; Nair, Rashmi S.; Steinmetz, Karen L.; Mirsalis, Jon C.; Nestmann, Earle R.; Barter, James A.

doi:10.1002/(sici)1520-6866(1998)18:6<309::aid-tcm5>3.0.co;2-p

Cited by 11 publications

(4 citation statements)

References 20 publications

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“…The NTP study found that liver tumor incidences were only increased in mice that also showed hepatotoxic effects, but not in low-dose female mice that had little or no hepatotoxicity. However, although a number of studies demonstrated mitogenic effects in the livers of exposed mice, some of the same studies as well as others found similar effects in the livers of rats, even though p-dichlorobenzene did not induce liver tumors in rats (Eldridge et al, 1992;James et al, 1998;Sherman et al, 1998;Umemura et al 1992Umemura et al , 1996Umemura et al , 1998. Additionally, some studies indicate that the mitogenic effects of p-dichlorobenzene may not be sustained throughout long-term exposure (Eldridge et al, 1992;Lake et al, 1997), and NTP (1987a) did not report hepatic hyperplasia among responses seen to be significantly elevated following chronic exposure to p-dichlorobenzene, although other hepatotoxic effects were found.…”

Section: P-dichlorobenzenementioning

confidence: 92%

“…The induction of liver cell proliferation in the absence of manifest hepatoxicity suggests that the proliferation is a response to mitogenic stimulation rather than compensatory regeneration consequent to cytotoxicity. Cellular proliferation and other changes were found in the kidney tubular epithelia of male rats, but not in female rats or mice of either gender, following short-term oral exposures to doses ≥150 mg/kg/d (Eldridge et al, 1992;Lake et al, 1997;Sherman et al, 1998;Umemura et al, 1992). The renal effects are consistent with the induction of α 2μ -globulin nephropathy in male rats by similar doses of p-dichlorobenzene in other acute oral studies (Charbonneau et al, 1989;Dietrich & Swenberg, 1991;Saito et al, 1996), but are not relevant to humans, as discussed later with the chronic toxicity and carcinogenicity data.…”

Section: P-dichlorobenzenementioning

confidence: 95%

“…Increased hepatocelluar proliferation, as measured by increased incorporation of bromodeoxyuridine (BrdU) or [ 3 H]thymidine into DNA-synthesizing liver cells, was demonstrated in rats and mice at doses ≥150 mg/kg/d in a number of single-dose and short-term oral studies that found no histological or other indications of overt liver damage (Eldridge et al, 1990(Eldridge et al, , 1992Lake et al, 1997;Sherman et al, 1998;Umemura et al, 1992Umemura et al, , 1996. The induction of liver cell proliferation in the absence of manifest hepatoxicity suggests that the proliferation is a response to mitogenic stimulation rather than compensatory regeneration consequent to cytotoxicity.…”

Section: P-dichlorobenzenementioning

confidence: 99%

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A Comparative Human Health Risk Assessment ofp-Dichlorobenzene-Based Toilet Rimblock Products Versus Fragrance/Surfactant-Based Alternatives

Aronson

Bosch

Gray

et al. 2007

Journal of Toxicology and Environmental Health, Part B

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A comparison of the human health risk to consumers using one of two types of toilet rimblock products, either a p-dichlorobenzene-based rimblock or two newer fragrance/surfactant-based alternatives, was conducted. Rimblock products are designed for global use by consumers worldwide and function by releasing volatile compounds into indoor air with subsequent exposure presumed to be mainly by inhalation of indoor air. Using the THERdbASE exposure model and experimentally determined emission data, indoor air concentrations and daily intake values were determined for both types of rimblock products. Modeled exposure concentrations from a representative p-dichlorobenzene rimblock product are an order of magnitude higher than those from the alternative rimblock products due to its nearly pure composition and high sublimation rate. Lifetime exposure to p-dichlorobenzene or the subset of fragrance components with available RfD values is not expected to lead to non-cancer-based adverse health effects based on the exposure concentrations estimated using the THERdbASE model. A similar comparison of cancer-based effects was not possible as insufficient data were available for the fragrance components.

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Section: P-dichlorobenzenementioning

confidence: 92%

Section: P-dichlorobenzenementioning

confidence: 95%

Section: P-dichlorobenzenementioning

confidence: 99%

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A Comparative Human Health Risk Assessment ofp-Dichlorobenzene-Based Toilet Rimblock Products Versus Fragrance/Surfactant-Based Alternatives

Aronson

Bosch

Gray

et al. 2007

Journal of Toxicology and Environmental Health, Part B

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“…6) One study evaluated the unscheduled DNA synthesis and replicative DNA synthesis by treating rats with p-DCB. 7) To examine whether p-DCB forms DNA adducts, we investigated the DNA adducts using the 32 P-postlabeling technique, which allows us to detect and quantitate adducts at the level of one adduct per 10 10 nucleotides. 8) This technique is more sensitive than injecting isotope to animal body in detecting DNA adducts.…”

Section: Introductionmentioning

confidence: 99%

Analysis of DNA Adducts after Exposure to 1,4-Dichlorobenzene by 32P-Postlabeling Technique.

Tian¹,

Madhusree²,

Fukuhara³

et al. 2001

JOURNAL OF HEALTH SCIENCE

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To evaluate the genetic toxicity of 1,4-dichlorobenzene (p-DCB), DNA adducts of p-DCB were analyzed in in vitro and in in vivo. In the in vitro study, calf thymus DNA (400 µg/ml) was mixed with p-DCB (100 µM), liver microsome (1 mg protein/ml) and an NADPHregenerating system. After incubation at 37°C for 1 hr, DNA was isolated and purified for DNA adduct analysis. There were no DNA adducts detected when p-DCB was metabolized by rat, mouse or human liver microsomes. In the in vivo study, Fischer 344 rats were given different kinds of cytochrome P450 (CYP) inducers and then injected with p-DCB. Twenty-four hr after injection, livers were collected from the rats for DNA adducts analysis. We did not find any p-DCB DNA adducts in rat livers pre-treated with ethanol, phenobarbital or 3-methylcholanthrene, respectively. In conclusion, no p-DCB DNA adducts were found either the in vitro or in vivo studies. In this study, we demonstrated that p-DCB is not genotoxic.

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1,4‐Dichlorbenzol [MAK Value Documentation in German language, 2018]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated 1,4‐dichlorobenzene [ 106‐46‐7 ] considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. In mouse liver, 1,4‐dichlorobenzene causes carcinoma after oral and inhalation exposure and is mitogenic and cytotoxic. In reliable studies it is not genotoxic. As a non‐genotoxic mechanism is of prime importance and genotoxic effects play at most a minor part, provided the maximum concentration at the workplace (MAK value) is observed, 1,4‐dichlororbenzene is now classified in Category 4 for carcinogenic substances. The chronic local NOAEC of 20 ml/m 3 for changes in the olfactory epithelium of the rat nose would correspond to a MAK value of 10 ml/m 3 . However, the most sensitive toxicological effect is hepatocellular hypertrophy with a LOAEL of 10 mg/kg body weight and day in an oral 52‐week study with dogs. Because of the low severity and incidence of the effect, a NAEL of 5 mg/kg body weight and day is assumed. This NAEL is scaled to a MAK value of 2 ml/m 3 . Since a systemic effect is critical, Peak Limitation Category II is assigned. As it is not known if the effects are due to the metabolites or 1,4‐dichlorobenzene itself, the default excursion factor of 2 is assigned. The NOAECs for developmental toxicity in rats and rabbits are 500 and 100 ml/m 3 , respectively, and the differences to the MAK value are sufficient. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and 1,4‐dichlorobenzene is assigned to Pregnancy Risk Group C. Skin contact may contribute significantly to systemic toxicity and 1,4‐dichlorobenzene remains designated with an “H” notation. Sensitization is not expected from the limited data.

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Evaluation of unscheduled DNA synthesis (UDS) and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene

Cited by 11 publications

References 20 publications

A Comparative Human Health Risk Assessment ofp-Dichlorobenzene-Based Toilet Rimblock Products Versus Fragrance/Surfactant-Based Alternatives

A Comparative Human Health Risk Assessment ofp-Dichlorobenzene-Based Toilet Rimblock Products Versus Fragrance/Surfactant-Based Alternatives

Analysis of DNA Adducts after Exposure to 1,4-Dichlorobenzene by 32P-Postlabeling Technique.

1,4‐Dichlorbenzol [MAK Value Documentation in German language, 2018]

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