Biomedical subjects

Marvin A Friedman

Publications and source records attributed to Marvin A Friedman.

9 recordsLinked to original sources

PubMed2006

Kinetics of elimination of urinary metabolites of acrylamide in humans.

Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objective of this study was to define the kinetics of elimination of AM and its metabolites following oral and dermal administration. This is the second part of a study in which metabolites and hemoglobin adducts of AM were determined in people (Fennell et al., 2005, Toxicol. Sci. 85, 447-459). (1,2,3-(13)C(3))AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples were collected at 0-2, 2-4, 4-8, 8-16, and 16-24 h following administration orally, or at 0-2, 2-4, 4-8, 8-16, and 16-24 h following each of three daily dermal doses. (13)C(3)-AM and its metabolites in urine, (13)C(3)-glycidamide, (13)C(3)-N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide, and (13)C(3)-N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine, were quantitated using liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 45.6, 49.9, and 39.9% of a 0.5, 1.0, and 3.0 mg/kg oral dose (0-24 h), respectively, and for 4.5% of the dose after 3 mg/kg was administered daily for 3 days dermally (0-4 days). These results indicate that after oral administration AM is rapidly absorbed and eliminated. The half-life estimated for elimination of AM in urine was 3.1-3.5 h. After dermal administration, AM uptake is slow. This study indicated that skin provides a barrier that slows the absorption of AM, and results in limited systemic availability following dermal exposure to AM.

Acetylcysteine↗

PubMed2005

Comparison of acrylamide metabolism in humans and rodents.

Acrylamide is metabolized by direct conjugation with glutathione or oxidation to glycidamide, which undergo further metabolism and are excreted in urine. In rats administered 3 mg/kg 1,2,3-13C3 acrylamide, 59% of the metabolites excreted in urine was from acrylamide-glutathione conjugation, whereas 25% and 16% were from two glycidamide-derived mercapturic acids. Glycidamide and dihydroxypropionamide were not detected at this dose level. The metabolism of acrylamide in humans was investigated in a controlled study with IRB approval, in which sterile male volunteers were administered 3 mg/kg 1,2,3-13C3 acrylamide orally. Urine was collected for 24 h after administration, and metabolites were analyzed by 13C NMR spectroscopy. At 24 h, urine contained 34% of the administered dose, and 75% of the metabolites were derived from direct conjugation of acrylamide with glautathione. Gycidamide, dihydroxypropionamide and one unidentified metabolite were also detected in urine. This study indicated differences in the metabolism of acrylamide between humans and rodents.

Acrylamide↗

PubMed2005

Effects of acrylamide on primary neonatal rat astrocyte functions.

The present study assessed biochemical endpoints indicative of acrylamide toxicity in astrocyte cultures derived from neonatal rat pups. Given earlier reports on the possible ability of acrylamide to induce astrocytomas in the Fischer 344 rat, we performed studies in neonatal rat astrocyte cultures from the Fischer 344 to assess the ability of acrylamide to induce astrocytic proliferation. Measurements on astrocytic proliferation included [3H]-leucine incorporation, [3H]-thymidine incorporation, and changes in proliferating cell nuclear antigen (PCNA). Although acrylamide (0.1 and 1 mM for 7, 11, 15, or 20 days) did not significantly (P > 0.05) affect [3H]-leucine or [3H]-thymidine incorporation, it significantly (P < 0.05) increased PCNA protein expression in astrocytes exposed to acrylamide for 15 and 20 days. Additional studies revealed that this effect on PCNA protein expression was not associated with activation of dopamine-2 (D2) receptors, given that quinpirole (10 microM added to cultures for the last hour of 7, 11, 15, or 20 days in culture), a selective D2 receptor agonist, did not produce results analogous to those seen with acrylamide treatment. Cotreatment of astrocytes with acrylamide (7, 11, 15, or 20 days) and the D2 receptor antagonist, sulpiride (1 microM for the last 6 h of exposure), also failed to reverse acrylamide's effect on PCNA protein induction. Taken together, these studies suggest that acrylamide promotes astrocytic cell proliferation in the CNS even though DNA synthesis did not appear stimulated.

Acrylamide↗

PubMed2004

Metabolism and hemoglobin adduct formation of acrylamide in humans.

Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.

Acrylamide↗

PubMed2004

Epidemiologic evidence for assessing the carcinogenicity of acrylamide.

Acrylamide (ACM) has recently been found in fried and baked foods, suggesting widespread public exposure. ACM is an industrial chemical that causes neurotoxicity in humans and an increase in benign tumors of the endocrine system of laboratory rats. The U.S. EPA and the International Agency for Research on Cancer (IARC) have designated ACM as a probable human carcinogen based on the bioassay data and evidence for a DNA reactive mechanism. We report here an assessment of the published epidemiological data with regard to exposure to ACM. The results of an epidemiology mortality study of heavily exposed workers published in 1999 failed to reveal any increase in total cancer in this workforce. The average total exposure in the exposed group was equivalent to over 100% of the estimated average lifetime dietary intake, assuming a U.S. diet. However, this epidemiologic information had limited power to detect modest increases in specific tumors of the type reported in the rodent studies. Although the mortality study could not have picked up the small increases in cancer or in specific cancer types predicted by EPA's linear extrapolation model, research on biochemical and physiological mechanisms suggests that EPA's assessment overstates the potency, and therefore, the risk from foods and other sources of exposure may be lower than previously anticipated.

Acrylamide↗

PubMed2003

The acute effects of acrylamide on astrocyte functions.

We assessed biochemical endpoints indicative of acute toxicity in neonatal rat primary astrocyte cultures exposed to acrylamide. Metallothionein (MT), glutamine synthetase (GS), glutamate/aspartate transporter (GLAST), and taurine transporter (tau-T) mRNA expression levels as well as cell volume were determined in astrocytes acutely treated with 0.1 and 1.0 mM acrylamide. Statistically significant changes in acrylamide treated astrocytes were noted for GS (0.1 mM) and GLAST (1.0 mM) mRNA expression levels. All other measurements were insignificant in comparison with controls, suggesting that astrocytic function is minimally compromised even at exceedingly high levels of acute acrylamide exposure.

Acrylamide↗

PubMed2002

Fast axonal transport: a site of acrylamide neurotoxicity?

The cellular and molecular site and mode of action of acrylamide (ACR) leading to neurotoxicity has been investigated for four decades, without resolution. Although fast axonal transport compromise has been the central theme for several hypotheses, the results of many studies appear contradictory. Our analysis of the literature suggests that differing experimental designs and parameters of measurement are responsible for these discrepancies. Further investigation has demonstrated consistent inhibition of the quantity of bi-directional fast transport following single ACR exposures. Repeated compromise in fast anterograde transport occurs with each exposure. Modification of neurofilaments, microtubules, energy-generating metabolic enzymes and motor proteins are evaluated as potential sites of action causing the changes in fast transport. Supportive and contradictory data to the hypothesis that deficient delivery of fast-transported proteins to the axon causes, or contributes to, neurotoxicity are critically summarized. A hypothesis of ACR action is presented as a framework for future investigations.

Acrylamide↗

PubMed2002

Acrylamide-induced cellular transformation.

Acrylamide is a monomer of polyacrylamide, whose products are used in biochemistry, the manufacture of paper, water treatment, and as a soil stabilizer. While polymeric acrylamide is nontoxic, the monomer can cause several toxic effects and has the potential for human occupational exposure. While acrylamide is not mutagenic in prokaryotic mutagenesis assays, chronic acrylamide treatment in rodents has been shown to produce tumors in both rats and mice. The mechanism for the induction of tumors by acrylamide is not known. In the present study, we examined the possibility that acrylamide might induce cellular transformation, using Syrian hamster embryo (SHE) cell morphological transformation as well as potential mechanisms for the cellular transformation. Results showed that treatment with 0.5 mM and higher concentrations of acrylamide continuously for 7 days induced morphological transformation. Cotreatment with acrylamide and N-acetyl-L-cysteine (NAC), a sulfhydryl group donor, resulted in the reduction of acrylamide-induced morphological transformation in SHE cells. Cotreatment with 1-aminobenzotriazole (ABT), a nonspecific P450 inhibitor, and acrylamide produced no change in morphological transformation when compared to acrylamide treatment only. Cotreatment with acrylamide and DL-buthionone-[S,R]-sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase, increased the percent of morphologically transformed colonies compared to acrylamide treatment alone. Acrylamide reduced GSH levels in SHE cells, and cotreatment with acrylamide and NAC prevented the acrylamide-induced reduction of GSH. BSO treatment with acrylamide enhanced the depletion of GSH. These results suggest that acrylamide itself, but not oxidative P450 metabolites of acrylamide appear to be involved in acrylamide-induced cellular transformation and that cellular thiol status (possibly GSH) is involved in acrylamide-induced morphological transformation.

Acetylcysteine↗

PubMedDate not supplied

Effects of acrylamide on rodent reproductive performance.

Acrylamide monomer causes peripheral neurotoxicity, mutagenicity, clastogenicity, male reproductive toxicity, prenatal lethality, and endocrine-related tumors in rodents. Acrylamide (and/or its metabolite glycidamide) binds to dopamine receptors and spermatid protamines and inhibits activity of kinesin and dyneine, resulting in interference with neuronal intracellular transport and sperm motility. Glycidamide binds to various proteins and DNA. Acrylamide at low doses decreases litter size, with rats more sensitive than mice. At higher doses, sperm morphology and motility and neurotoxicity are affected, which decreases mating frequency. Acrylamide does not affect female reproduction (females exhibit neurotoxicity). Dominant lethal mutations cause decreased newborn litter size. The mechanisms of action appear to be: (1) acrylamide/glycidamide binding to spermatid protamines, causing dominant lethality and effects on sperm morphology; and (2) acrylamide binding to motor proteins, causing distal axonopathy, including hindlimb weakness/paresis, and effects on mounting, sperm motility, and intromission. Glycidamide-induced mutations appear to play no role in reproductive or neurologic toxicity.

Acrylamide↗