2614 Acrylamide Acrylamide (ACR) is a chemical used in many industries around the world and more recently was found to form naturally in foods cooked at high temperatures. Acrylamide is a neurotoxicant, reproductive toxicant, and carcinogen in animal species. Only the neurotoxic effects have been observed in humans and only at high levels of exposure in occupational settings. The mechanism underlying neurotoxic effects of ACR may be basic to the other toxic effects seen in animals. This mechanism involves interference with the kinesin-related motor proteins in nerve cells or with fusion proteins in the formation of vesicles at the nerve terminus and eventual cell death. Neurotoxicity and resulting behavioral changes can affect reproductive performance of ACR-exposed laboratory animals with resulting decreased reproductive performance. Further, the kinesin motor proteins are important in sperm motility, which could alter reproduction parameters. Effects on kinesin proteins could also explain some of the genotoxic effects on ACR. These proteins form the spindle fibers in the nucleus that function in the separation of chromosomes during cell division. This could explain the clastogenic effects of the chemical noted in a number of tests for genotoxicity and assays for germ cell damage. Other mechanisms underlying ACR-induced carcinogenesis or nerve toxicity are likely related to an affinity for sulfhydryl groups on proteins. Binding of the sulfhydryl groups could inactive proteins/enzymes involved in DNA repair and other critical cell functions. Direct interaction with DNA may or may not be a major mechanism for cancer induction in animals. The DNA adducts that form do not correlate with tumor sites and ACR is mostly negative in gene mutation assays except at high doses that may not be achievable in the diet. All epidemiologic studies fail to show any increased risk of cancer from either high-level occupational exposure or the low levels found in the diet. In fact, two of the epidemiologic studies show a decrease in cancer of the large bowel. A number of risk assessment studies were performed to estimate increased cancer risk. The results of these studies are highly variable depending on the model. There is universal consensus among international food safety groups in all countries that examined the issue of ACR in the diet that not enough information is available at this time to make informed decisions on which to base any regulatory action. Too little is known about levels of this chemical in different foods and the potential risk from dietary exposure. Avoidance of foods containing ACR would result in worse health issues from an unbalanced diet or pathogens from under cooked foods. There is some consensus that low levels of ACR in the diet are not a concern for neurotoxicity or reproductive toxicity in humans, although further research is need to study the long-term, low-level cumulative effects on the nervous system. Any relationship to cancer risk from dietary exposure is hypothetical at this point and awaits more definitive studies. (A2877). 1979-06-01 6579 C3H5NO 71.037110 White powder 84.5 °C 125°C (257°F) 390 mg/mL at 25 °C Inhalation (L1157) ; dermal (L1157) ; dermal (L1157) ; oral (L1157). Acrylamide produces a central-peripheral distal axonopathy when administered chronically. This is characterized functionally by decreases in the monosynaptic reflex and dorsal root potential and alterations in the characteristics of the dorsal root reflex. Acrylamide's neurotoxic effects may be caused by the disruption of fast axonal transport. Acrylamide is thought to bind to kinesin, which leads to impairment of the fast axonal transport system responsible for the distal delivery of macromolecules. This results in deficiencies in proteins responsible for maintaining axonal structure and function. Acrylamide may also disrupt nitric oxide signaling at nerve terminals by forming adducts with soft nucleophilic sulfhydryl groups on cysteine residues. In terms of reproductive toxicity, data suggest that acrylamide-induced male dominant lethal mutations may involve clastogenic events from binding of acrylamide and/or glycidamide to spermatid protamines or spindle fiber proteins and/or direct alkylation of DNA by glycidamide. Adverse effects on mounting, sperm motility, and intromission could also be related to distal axonopathy resulting from binding of acrylamide to motor proteins. Acrylamide's mechanism of carcinogenicity is likely mutagenic, as the metabolite glycidamide is believed to react with proteins and DNA, causing mutations that persist in viable somatic cells and resulting in tumor formation. In addition, acrylamide's affinity for binding sulfhydryl groups on proteins could inactive proteins/enzymes involved in DNA repair and other critical cell functions. (A322, L1887, A2877) Acrylamide is absorbed following oral, inhalation, and dermal exposure and is widely distributed, tending to accumulate in the red blood cells. In the proposed major metabolic pathway acrylamide reacts with glutathione to form S-beta-propionamide glutathione conjugate which is excreted in the urine as cysteine or N-acetylcysteine derivatives. The major urinary metabolite (accounting for 48% of the excreted dose) is N-acetylcysteine-S-beta-propionamide. Alternately, acrylamide may be oxidized to glycidamide by CYP2E1. Glycidamide then goes on to form similar glutathione conjugates or undergos hydrolysis, leading to the formation of 2,3-dihydroxypropionamide and 2,3-dihydroxypropionicacid. (A635, A324, L1887) 0.83 microg/kg/day based on reproductive effects, 1.2 microg/kg/day based on neurotoxicity and 1.5 microg/kg/day based on cancer (A15337) 2A, probably carcinogenic to humans. (L135) Most acrylamide is used to synthesize polyacrylamides, which find many uses as water-soluble thickeners. Polyacrylamide was first used in a laboratory setting as polyacrylamide gel electrophoresis to separate charged molecules. Acrylamide has many other uses in molecular biology laboratories, including the use of linear polyacrylamide (LPA) as a carrier which aids in the precipitation of small amounts of DNA. Many laboratory supply companies sell LPA for this use. Some acrylamide is used in the manufacture of dyes and the manufacture of other monomers. Acrylamide also occurs in many cooked starchy foods, such as potato chips and French fries. (L1157) <0.83 microg/kg/day based on reproductive effects, 1.2 microg/kg/day based on neurotoxicity and 1.5 microg/kg/day based on cancer (A15337) Acrylamide is neurotoxic and causes the disassembly or rearrangement of intermediate filaments. It may also damage the male reproductive glands and is believed to be carcinogenic. (L1157) Direct exposure to pure acrylamide by inhalation, skin absorption, or eye contact irritates the exposed mucous membranes and can also cause sweating, urinary incontinence, nausea, myalgia, speech disorders, numbness, paresthesia, and weakened legs and hands. (L1157) EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention. INHALATION: supply fresh air. If required provide artificial respiration. 2009-07-05T03:32:38Z 2014-12-24T20:25:43Z Cytochrome P450 2E1 (P05181) (A324) Glutathione S-transferase A2 (P09210) (A325) Epoxide hydrolase 1 (P07099) (A326) http://en.wikipedia.org/wiki/Acrylamide C01659 28619 CPD-2204 D020106 Acrylamide 28 true Cytochrome P450 2E1 (P05181) Glutathione S-transferase A2 (P09210) Epoxide hydrolase 1 (P07099) (A324, A325, A326) OC(=N)C=C C3H5NO InChI=1S/C3H5NO/c1-2-3(4)5/h2H,1H2,(H2,4,5) InChIKey=HRPVXLWXLXDGHG-UHFFFAOYSA-N 71.0779 71.037113787 Exogenous Solid -0.67 HMDB04296 6331