Comparative Metabolism, Bioavailability, and Toxicokinetics of Benzo[ a ]pyrene in Rats After Acute Oral, Inhalation, and Intravenous Administration

Ramesh, Aramandla; Hood, Darryl B.; Inyang, Frank; Greenwood, Michael; Nyanda, Alfred M.; Archibong, Anthony E.; Knuckles, Maurice E.

doi:10.1080/10406630290104121

Cited by 44 publications

(29 citation statements)

References 3 publications

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“…The epoxides formed may either spontaneously rearrange, undergo hydrolysis by epoxide hydrolase, or be conjugated by related enzymes to benzo(a)pyrene 7,8-dihydrodiol, 9,10-epoxide (BPDE), which require recycling of PAH-diols through the microsomal monooxygenase system (Baird and Ralston, 1997). Ramesh et al (2002) demonstrated significant levels of BaP metabolites in the testis of exposed rats. The substantial presence of BaP and some of its metabolites in the male gonads even after 8 hours (oral), or 4 hours (inhalation) post-exposure , suggests their incorporation into the Leydig lipogenic tissue and possible alteration of normal steroidogenic and spermatogenic function.…”

Section: Introductionmentioning

confidence: 93%

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Ramesh

Inyang

Lunstra

et al. 2008

Experimental and Toxicologic Pathology

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The objective of this study was to evaluate the reproductive risk associated with exposure of adult male Fisher-344 rats to inhaled benzo(a)pyrene (BaP). Rats were assigned randomly to a treatment or control group. Treatment consisted of sub-chronic exposure of rats via inhalation to 75μg BaP/ m 3 , 4 hours daily for 60 days, while control animals were unexposed (UNC). Blood samples were collected immediately after the cessation of exposures (time 0) and subsequently at 24, 48, and 72 hrs, to assess the effect of bioavailable BaP on plasma testosterone and luteinizing hormone (LH) concentrations. Rats were sacrificed after the last blood collection. Testes were harvested, weighed and prepared for histology and morphometric analysis, and cauda epididymides were isolated for the determination of progressive motility and density of stored spermatozoa. BaP exposure reduced testis weight compared with UNC (Mean ± SE; 2.01 ± 0.11 vs. 3.04 ± 0.16 g; P< 0.025), and caused significant reductions in the components of the steroidogenic and spermatogenic compartments of the testis. Progressive motility and mean density of stored spermatozoa were reduced (P< 0.05). Plasma testosterone concentrations were decreased by two-thirds in BaPexposed rats throughout the time periods studied compared with those of their UNC counterparts (P< 0.05), concomitant with increased concentrations of LH in BaP-exposed rats (P< 0.05). These data suggest that sub-chronic exposure to inhaled BaP contribute to reduced testicular and epididymal function in exposed rats.

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Section: Introductionmentioning

confidence: 93%

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Ramesh

Inyang

Lunstra

et al. 2008

Experimental and Toxicologic Pathology

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“…BaP is rapidly distributed to the stomach in mice exposed to BaP via oral or topical administration (Carlson et al, 1986). Oral BaP exposure in rats leads to more rapid distribution of BaP to blood plasma compared with inhalation exposure; for example, BaP concentrations in the serum peaked 1 and 8 hours following oral and inhalation exposures to BaP, respectively (Ramesh et al, 2002). Lung and liver were the major organs in which BaP metabolites were detected following oral, inhalation and intravenous exposures of rats to BaP (Ramesh et al, 2002).…”

Section: Traditional Risk Assessment Approach (Ra1)mentioning

confidence: 99%

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Moffat

Chepelev

Labib

et al. 2015

Critical Reviews in Toxicology

138

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Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lung 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.

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“…Adverse effects of prenatal BaP exposure on fetal development have been much investigated, and inhalation exposure of pregnant rats or mice of 25-100 lg/l BaP decreased the numbers of live pups at birth (Ramesh et al 2002;Wu et al 2003). pregnant mice also caused measurable changes in enzymes, i.e., pyruvate kinase and lactic acid dehydrogenase, in the lungs of the fetuses (Rady et al 1981).…”

Section: Sublethal Toxicitymentioning

confidence: 99%

Chronic Toxicity Thresholds for Sediment-Associated Benzo[a]pyrene in the Midge (Chironomus dilutus)

Huang³

et al. 2014

Arch Environ Contam Toxicol

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Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in aquatic ecosystems and have been shown to be one of the causes of sediment toxicity to benthic invertebrates. Benzo[a]pyrene (BaP) was selected as a representative for the PAH family of compounds for developing chronic sediment toxicity thresholds for Chironomus dilutus. Life-cycle toxicity testing was initiated using newly hatched midge larvae and terminated until hatch of the second generation. Median lethal concentrations were 92.5 ± 19.6 and 56.9 ± 1.76 lg/g organic carbon (OC) after exposing midges to sedimentassociated BaP for 20 days (before pupation) and 43 days (end of test), respectively. Sublethal toxicity was described as 5 and 50 % effect concentrations (EC5 and EC50), and these were 6.63 ± 0.82 and 41.1 ± 1.61 lg/g OC for growth reduction at 20 days, respectively. Impairments of emergence and reproduction of C. dilutus were also assessed at the end of the testing, and the EC5 and EC50 values were 3.41 ± 0.53 and 26.9 ± 1.43 lg/g OC for emergence and 2.18 ± 0.34 and 13.4 ± 1.13 lg/g OC for reproduction, respectively. In addition, bioavailability-based chronic toxicity thresholds were also established using Tenax-extractable BaP concentrations. Although more environmentally relevant, data regarding chronic toxicity are less available than those regarding acute toxicity. Therefore, establishing numeric chronic toxicity thresholds for sediment-associated BaP with the consideration of the bioavailability would improve the accuracy of assessing PAH-related sediment toxicity.

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Comparative Metabolism, Bioavailability, and Toxicokinetics of Benzo[ a ]pyrene in Rats After Acute Oral, Inhalation, and Intravenous Administration

Cited by 44 publications

References 3 publications

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Chronic Toxicity Thresholds for Sediment-Associated Benzo[a]pyrene in the Midge (Chironomus dilutus)

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