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The unexpected finding that humans are regularly exposed to relatively high doses of acrylamide (AA) through normal consumption of cooked food was a result of systematic research and relevant developments in methodology over decades, as well as a chain of certain coincidences. The present paper describes the scientific approach, investigations and events leading to the discovery of the formation of AA during cooking of foods. In addition, related issues concerning assessment, communication and management of cancer risks and associated ethical questions raised by the finding of the presence of AA in foods will be discussed.

Acrylamide (AA) monomer is used in numerous chemical industries and is a contaminant in potato- and grain-based foods prepared at high temperatures. Although experimental animal studies have implicated carcinogenicity and reproductive toxicity as possible consequences of exposure, neurotoxicity is the only outcome identified by epidemiological studies of occupationally exposed human populations. Neurotoxicity in both humans and laboratory animals is characterized by ataxia and distal skeletal muscle weakness. Early neuropathological studies suggested that AA neurotoxicity was mediated by distal axon degeneration. However, more recent electrophysiological and quantitative morphometric analyses have identified nerve terminals as primary sites of AA action. A resulting defect in neurotransmitter release appears to be the pathophysiological basis of the developing neurotoxicity. Corresponding mechanistic research suggests that AA impairs release by adducting cysteine residues on functionally important presynaptic proteins. In this publication we provide an overview of recent advances in AA research. This includes a discussion of the cumulative nature of AA neurotoxicity and the putative sites and molecular mechanisms of action.

Since April 2002, when the Swedish National Food Administration first reported its finding of elevated levels of the substance acrylamide in commonly consumed foods (Swedish National Food Administration, 2002), there has been considerable debate about the health effects of dietary exposure to acrylamide. In particular, researchers have speculated on whether the amount of acrylamide consumed through the typical diet could increase the risk of cancer in humans. In this paper, we review the epidemiological data to date examining dietary acrylamide in relation to cancer risk. We highlight the strengths and limitations of using epidemiology to address this public health question. Finally, we provide an overview of future directions of epidemiological research on the health effects of dietary acrylamide.

Acrylamide is a monomer of polyacrylamide, used in biochemistry, in paper manufacture, in water treatment, and as a soil stabilizer. The monomer can cause several toxic effects and has the potential for human exposure either through the environment or from occupational exposure. Recently, additional concern for the potential toxicity of acrylamide in humans has arisen with the finding of acrylamide formation in some processed foods. It has been established that following chronic exposure, rats exhibited an increase in the incidence of adrenal pheochromocytomas, testicular mesotheliomas, thyroid adenomas and mammary neoplasms in F344 rats. This has raised increased concerns regarding the carcinogenic risk to humans from acrylamide exposure. Studies examining the DNA reactivity of acrylamide have been performed and have had differing results. The tissue and organ pattern of neoplastic development seen in the rat following acrylamide exposure is not consistent with that seen with other strictly DNA reactive carcinogens. Based on the pattern of neoplastic development, it appears that acrylamide is targeting endocrine sensitive tissues. In the current monograph, studies on the effect of acrylamide on DNA reactivity and on altered cell growth in the target tissues in the rat are reported. DNA synthesis was examined in F344 rats treated with acrylamide (0, 2, or 15 mg/kg/day) for 7, 14, or 28 days. Acrylamide increased DNA synthesis in the target tissues (thyroid, testicular mesothelium, adrenal medulla) at all doses and time points examined. In contrast, in a non-target tissue (liver), no increase in DNA synthesis was seen. Examination of DNA damage using single cell gel electrophoresis (the Comet assay) showed an increase in DNA damage in the target tissues, but not in non-target tissue (liver). In addition, a cellular transformation model, (the Syrian Hamster Embryo (SHE) cell morphological transformation model), was used to examine potential mechanisms for the observed carcinogenicity of acrylamide. SHE cell studies showed that glutathione (GSH) modulation by acrylamide was important in the cell transformation process. Treatment with a sulfhydryl donor compound (NAC) reduced acrylamide transformation while depletion of GSH (BSO) resulted in an enhancement of transformation. In summary, acrylamide caused both an increase in DNA synthesis and DNA damage in mammalian tissues and cells suggesting that DNA reactivity and cell proliferation, in concert, may contribute to the observed acrylamide-induced carcinogenicity in the rat and has implication on the possible risk for human neoplasm development.

This paper attempts to assess possible risks that may result from human exposure to dietary intake of acrylamide.

Acrylamide (AA) is a carcinogen as demonstrated in animal experiments, but the relevance for the human situation is still unclear. AA and its metabolite glycidamide (GA) react with nucleophilic regions in biomolecules. However, whereas AA and GA react with proteins, DNA adducts are exclusively formed by GA under conditions simulating in vivo situations. For risk assessment it is of particular interest to elucidate whether AA or GA within the plasma concentration range resulting from food intake are “quenched” by preferential reaction with non-critical blood constituents or whether DNA in lymphocytes is damaged concomitantly under such conditions. To address this question dose- and time-dependent induction of hemoglobin (Hb) adducts as well as genotoxic and mutagenic effects by AA or GA were studied in human blood as a model system.

Food is assumed to be one major source of acrylamide exposure in the general population. Acrylamide exposure is usually assessed by measuring hemoglobin adducts of acrylamide and its primary metabolite glycidamide as biomarkers. Little is known about the impact of acrylamide in food on biomarkers of acrylamide exposure. Therefore, CDC is conducting a feeding study to investigate the effect of consumption of endogenous acrylamide in food on biomarkers of acrylamide exposure. As part of this study, we performed a pilot study to obtain further information on the magnitude of the changes in biomarker levels after consumption of high amounts of potato chips (21 ounces) over a short period of time (1 week) in non-smokers. After 1 week, biomarkers levels increased up to 46% for acrylamide adducts and 79% for glycidamide adducts. The results indicate that changes in biomarker levels due to consumption of potato chips can be detected. However, because of the design of this pilot study, the observed magnitude of change cannot be generalized and needs to be confirmed in the main study.

Hemoglobin adducts of acrylamide and its primary metabolite, glycidamide are used as biomarkers of acrylamide exposure. Several methods for analyzing these biomarkers in blood have been described previously. These methods were developed to analyze small numbers of samples, not the high sample throughput that is needed in population screening. Obtaining data on exposure of the US population to acrylamide through food and other sources is important to initiate appropriate public health activities. As part of the Centers for Disease Control and Prevention biomonitoring activities, we developed a high throughput liquid chromatography tandem mass spectrometry (LC/MS/MS) method for hemoglobin adducts of acrylamide. The LC/MS/MS method consists of using the Edman reaction and isolating the reaction products by protein precipitation and solid-phase extraction (SPE). Quantitation is achieved by using stable-isotope labeled peptides as internal standards. The method is performed on an automated liquid handling and SPE system. It provides good sensitivity in the low-exposure range as assessed in pooled samples and enables differentiation between smokers and non smokers.

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-^13C_3 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-^13C_3 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.

A pharmacokinetic (PBPK) model has been developed for acrylamide (AMD) and its oxidative metabolite, glycidamide (GLY), in the rat based on available information. Despite gaps and limitations to the database, model parameters have been estimated to provide a relatively consistent description of the kinetics of acrylamide and glycidamide using a single set of values (with minor adjustments in some cases). Future kinetic and mechanistic studies will need to focus on the collection of key data for refining certain model parameters and for model validation, as well as for conducting studies that elucidate the mechanism of action. Development of a validated human AMD/GLY PBPK model capable of predicting target tissue doses at relevant dietary AMD exposures, in combination with expanding data on modes of action, should allow for a substantive improvement in the risk assessment of acrylamide in food.