Minireview on the toxicity of dietary acrylamide

Minireview on the toxicity of dietary acrylamide, Minireview on the toxicity of dietary acrylamide, Minireview on the toxicity of dietary acrylamide, Minireview on the toxicity of dietary acrylamide.

Available online at www.sciencedirect.com Food and Chemical Toxicology 46 (2008) 1360–1364 www.elsevier.com/locate/foodchemtox Minireview on the toxicity of dietary acrylamide Wolfram Parzefall * Research Unit Toxicology and Prevention, Division Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, A-1090 Vienna, Austria Received 11 May 2007; accepted 20 August 2007 Abstract Acrylamide is a commodity chemical with many industrial and laboratory uses It is also formed from carbohydrate and amino acid containing food by heating (primarily in fried potato products, bread, coffee) Neurotoxicity was detected as the primary toxic effect after occupational exposure In rats and mice AA is toxic for reproduction and development and to male germ cells, is genotoxic through a reactive metabolite, glycidamide, and carcinogenic to several organs Epidemiological studies did not point to an association between either occupational or dietary exposure and an excess of cancer incidence Health risks of the general population are based on an average exposure to lg/kg bw/day increasing for high consumers to lg/kg bw/day For average consumers a margin of exposure of 200 for neurotoxicity can be regarded as sufficiently protective However, a margin of 300 for carcinogenic risks appears not sufficient when applying a precautionary principle This is also illustrated when the benchmark dose lower confidence limit for cancer is divided by an uncertainty factor of 300, which arrives at a tolerable daily intake of lg/kg bw/day, and thus is in the range of average consumption Further measures to minimize acrylamide formation in food should therefore be explored to reduce human exposure Ó 2007 Elsevier Ltd All rights reserved Keywords: Acrylamide; Food; Risk assessment; Neurotoxicity; Genotoxicity; Carcinogenicity Introduction Acrylamide (AA, CAS Reg No 79-06-1) is a chemical intermediate used for the production of polyacrylamides These are utilized in the synthesis of dyes; in copolymers for contact lenses; in construction of dam foundations, tunnels, and sewers Polymers are also used as additives for water treatment, enhanced oil recovery, flocculants, papermaking aids, thickeners, soil conditioning agents, sewage and waste treatment, ore processing, permanentpress fabrics Further uses are in oil well drilling fluids, for soil stabilization, as dye acceptors, as polymers for Abbreviations: AA, acrylamide; BMDL, benchmark dose lower confidence limit; GA, glycidamide; LED10, lower exposure dose for a 10% risk; LOAEL, lowest-observed-effect-level; MOE, margin of exposure; NOAEL, no-observed-effect-level; POD, point of departure; RfD, reference dose; TDI, tolerable daily intake * Tel.: +43 4277 65136; fax: +43 4277 65159 E-mail address: wolfram.parzefall@meduniwien.ac.at 0278-6915/$ - see front matter Ó 2007 Elsevier Ltd All rights reserved doi:10.1016/j.fct.2007.08.027 promoting adhesion, for increasing the softening point and solvent resistance of resins, as components of photopolymerizable systems, and as cross-linking agents in vinyl polymers The monomer itself is handled in many molecular biology and genetic engineering laboratories for the preparation of electrophoresis gels by a large number of scientists and assistant personnel Increasing demands on AA are reported in the recent years, reaching 75 million kg in 1998 and 93 million kg in 2003 (NIH, 2007) Besides the industrial and laboratory uses the general population is exposed to varying amounts of AA via the diet Attention to this fact was drawn initially by Tareke et al (2000, 2002) These reports initiated an intense analytical survey of food items and mechanistic studies to identify conditions for formation of AA Exposure to AA and its toxic effects have been evaluated by IARC (1994) and by WHO/JECFA (2005) Special issues have also dealt with the general toxicity of AA (Mutation Research, 2005) and with its nutritional risks W Parzefall / Food and Chemical Toxicology 46 (2008) 1360–1364 (Alexander, 2006), and a comprehensive review on all aspects of AA toxicity including mechanisms and risk assessment has recently appeared (Shipp et al., 2006) The current minireview will mainly deal with human health risks due to AA ingested with food and compare the risks as assessed with different models Exposure Historically AA was found as an adduct to the N-terminus of hemoglobin (Hb) in exposed workers N-(2carbamoylethyl)valine was identified as the main adduct However, in occupationally unexposed non-smokers the N-(2-carbamoylethyl)valine adduct was also regularly detected (IARC, 1994; Bergmark, 1997) A subsequent animal experiment clearly showed that fried rat chow prompted higher N-(2-carbamoylethyl)valine levels than untreated feed Further analytical studies revealed that processing of food rich in starch and protein is the main source of AA Specifically, glucose and the amino acids asparagine > glutamine > methionine > cysteine, in falling efficiency, provided the essential ingredients for AA formation when heated above 120 °C (Mottram et al., 2002; Stadler et al., 2002) In the processing of food, this known as browning or Maillard reaction Since then marketed and home-made food was more closely monitored Commercial producers tried to change their production processes to reduce AA formation Analytical data show that the following food items are major contributors in Western diet to total exposure to AA: 13– 39% coffee, 10–30% bread and rolls/toasts, 16–30% potato chips, 6–46% potato crisps, 10–20% pastry and sweet biscuits According to the most recent data, average human intake is estimated to be 0.4 lg/kg bw/day from two years of age onwards However, intake may vary widely from 0.3 to lg/kg bw/day or may reach even lg/kg bw/day at the 99th percentile (WHO/JECFA, 2005) The concluding estimate of average daily human intake was lg/kg bw/ day and for high consumers it amounted to lg/kg bw/ day Toxicokinetics Ingested AA is taken up into the circulation and excreted mainly with the urine Sixty percentage of a dose of 0.94 mg contained in a meal of volunteers was recovered from urine within 72 h (Fuhr et al., 2006) Several metabolites were identified The majority of AA is conjugated with glutathione and less is activated by cytochrome P-450 CYP2E1 to a reactive epoxy compound, glycidamide (GA) GA is further metabolized and detoxified by glutathione On ground of the metabolites analysed, the authors concluded that the relative internal exposure for glycidamide from dietary acrylamide in humans amounts to only one quarter to one half of that in rats or mice This is important with respect to risk assessment because in humans there will be less reaction products of glycidamide, e.g less DNA and Hb adducts The latter is used as a biomarker of internal exposure (see above) Experiments in 1361 rats, mice, dogs, and pigs have shown that AA is rapidly distributed to all tissues including the testes, and after passing the placental barrier AA reaches the fetus as well The Hb adduct carbamoyl-ethyl-valine was measured to give an orientation on internal exposure levels As such the adduct provides also a bridge to endpoints of potential toxicity Average adduct levels in laboratory workers were 54 pmol/g globin and 152 in cigarette smokers, whereas background levels amounted to 31 pmol/g globin, corresponding to an estimated daily intake of 0.8 lg/kg bw/ day (Hagmar et al., 2005) The Hb adduct of GA, carbamoyl-hydroxyethyl-valine, was detected at maximally 12% of the AA-Hb adduct This internal dose metric confirms that practically all humans are exposed to AA Toxicodynamics The main toxic endpoints of AA are known as neurotoxicity in humans and animals, developmental and reproductive toxicity in rodents, and genotoxicity and carcinogenicity in rodents Neurotoxicity of AA is known from accidental intoxications and from chronic occupational exposures Although primarily peripheral neuropathies were reported other parts of the nervous system are also affected, like cerebellar Purkinje cell damage and degradation of distal axons in the central nervous system and peripheral nervous system The degradation of terminal nerves has been reported to lead to impairment of cognitive functions and damage to the cerebral cortex, thalamus and hippocampus Most of the neurotoxic effects could be reproduced in animal studies Chronic dose-response studies (2 years by drinking water) revealed a NOAEL for microscopic degenerative nerve changes of 500 lg/kg bw/day and a LOAEL of 2000 lg/ kg bw/day (Johnson et al., 1986) In an earlier 90-day study (AA in drinking water) a NOAEL of 200 and a LOAEL of 1000 lg/kg bw/day were reported (Burek et al., 1980) A direct comparison of the animal NOAEL with data from humans based on the internal dose measure of AA-Hb adducts in both species has been attempted (Calleman, 1996) and for exposed persons a NOAEL of 80 lg/ kg bw/day was estimated by calculations This value was considered uncertain because of a more than 10-fold difference between measured and calculated plasma levels of free AA in this toxicokinetics model (Shipp et al., 2006) Toxicity to reproduction has been observed in experimental animals Doses of 0, 0.5, 2, and mg/kg were administered in the drinking water The parameters measured in multigeneration studies were implantations and live pups per litter in the parental generation, and live pups per litter in the F1 generation In dominant lethal studies the number of live and lethal implantations per litter were evaluated From this study a NOAEL of 2000 lg/kg/day was derived (Tyl et al., 2000), which is the lowest NOAEL available from reliable studies Developmental toxicity was only detected at doses which also produced maternal toxicity and neurotoxicity (i.e up to 15 mg/kg/day) 1362 W Parzefall / Food and Chemical Toxicology 46 (2008) 1360–1364 Genotoxicity AA itself is of low DNA reactivity under in vitro conditions but after metabolic activation specific DNA adducts on the basis of GA were observed (Gamboa et al., 2003) This adduct is present in almost all rodent organs after AA administration AA was not mutagenic in bacterial systems In contrast, GA the primary metabolite was mutagenic even without metabolic activation Gene mutations were induced in mammalian Chinese hamster ovary cells and in transgenic mice (lacZ Muta Mouse and Big Blue Mouse) Chromosomal aberrations in the bone marrow were seen in one mouse strain but not in others, and micronuclei were increased in the bone marrow of mice but not of rats AA is one of the few chemical compounds which induce germ cell mutations Germ cell toxicity was observed in several studies with male mice and rats In one of these studies single i.p doses of AA induced a timeand dose-dependent response in unscheduled DNA synthesis of testicular DNA which was also paralleled by binding of radiolabeled AA to testicular DNA (Sega et al., 1990) In other studies, positive outcomes were detected with the following endpoints: increases in strand breaks in spermatids, decrease in elongated spermatid fraction, DNA strand breaks in sperm, sister chromatid exchange in differentiating spermatogonia (no clear dose-response), spermatid micronucleus after subchronic treatment in rats, specific locus mutations (Russell et al., 1991) All effects were seen at doses of 25 mg/kg and higher However, it is clearly demonstrated that AA reaches the germline and is toxic to male germ cells In conclusion, AA is a genotoxic and mutagenic food constituent which acts mainly through its reactive metabolite GA As in rodents, where the genotoxicity of AA is clearly established, binding of AA metabolites is also found in human Hb as a surrogate marker for internal dose (see above, Hagmar et al., 2005) AA-adducts at Hb were significantly higher in smokers than in non-smokers In nonsmokers AA-adduct levels varied by a factor of between persons with low and high dietary intake of AA These findings show that AA is bound to macromolecules in exposed humans and suggest that a genotoxic risk may exist However, a literature search did reveal nothing about binding of AA metabolites to human DNA in vivo Whereas in vitro human lymphocyte DNA is damaged by 0.5–50 lM AA which induced mainly alkali-labile sites as detected in the Comet assay (Blasiak et al., 2004) During extended incubation for 60 these lesions disappeared which is interpreted as an indication for DNA repair Thus, AA may well contribute to tumorigenesis in humans Carcinogenicity The carcinogenicity of AA has been evaluated by IARC (1994) and reviewed (Besaratinia and Pfeifer, 2007; Carere, 2006; Rice, 2005; Shipp et al., 2006; WHO, 2005) Since then epidemiological studies were updated or new studies were published Occupational exposure to AA appears to be the most relevant with respect to human cancer risk However, none of four older epidemiological studies uncovered significant tumor risks An original study by Collins et al (1989) has been updated by follow up (Marsh et al., 1999, 2007) No significant increases due to AA were found An increase in respiratory cancer had to be attributed to exposure to hydrochloric acid The discovery of AA in food has fuelled an intense search for possibly dietary exposure related cancer In a prospective study among 61467 women of the Swedish Mammography Cohort exposure was estimated by the major food constituents known to contain AA After correction for confounders, no positive association between AA intake and colorectal, colon or rectal cancer could be established (Mucci et al., 2006) Earlier studies of Mucci had also found no evidence that dietary AA would contribute to the risk for renal cancer (Mucci et al., 2004) or breast cancer (Mucci et al., 2005) in a cohort of Swedish women Another large case control study has examined Italian and Swiss hospital-based cases of tumors of several organs including oral cavity/pharynx, larynx, esophagus, colon/ rectum, breast, ovary, and prostate No consistent association between AA intake and tumorigenesis was found (Pelucchi et al., 2006) In conclusion, none of the epidemiological studies showed convincing contributions of AA to human tumorigenesis in all probability because of their very limited statistical power For this and for other grounds the studies on dietary exposure to AA have been criticized (Rice, 2005; Besaratinia and Pfeifer, 2007) It is no question that dietary studies are hampered, first, by poorely defined exposure to AA and, second, by co-exposure to several other food borne carcinogens These comprise primarily nitrosamines, polycyclic aromatic hydrocarbons, heterocyclic amines, not to forget natural contaminants like mold toxins and plant constituents which have been characterized as rodent carcinogens as compiled by Ames et al (1990) and also life-style drugs like alcohol The latter may interfere with AA metabolism by inducing CYP2E1 All these carcinogens may add to the tumor risk attributed to diet as estimated by Doll and Peto (1981) Significant increases in tumors in female and male mice and rats have been found In Sencar mice tumors of the skin developed after topical or oral treatment with AA and subsequent promotion by tetradecanoyl phorbol acetate In sensitive A/J mice lung tumors were initiated (Bull et al., 1984) In male and female rats, tumors of the thyroid gland were observed, in females tumors of the central nervous system, oral cavity, mammary gland, uterus and clitoral gland, and in males peritoneal mesotheliomas of the testis AA appears to be a multi-organ carcinogen in rodents This is consistent with its distribution throughout the whole body However, it is noteworthy that there are no W Parzefall / Food and Chemical Toxicology 46 (2008) 1360–1364 1363 Table Experimental limits for AA toxicity related to human exposure Effect Neurotoxicity Toxicity to reproduction and development Carcinogenesis Carcinogenesis a b Experimental limit (lg/kg bw/day) 200 (or 500) (NOAEL) 2000 (NOAEL) 300 (BMDL) 440 (POD as LED10) Margin of exposure Average intakea High intakeb 200 2000 300 440 50 500 75 110 RfD or TDI (lg/kg bw/day) Uncertainty factor 0.67 20 1.4 300 100 300 300 Average intake: lg/kg/day High intake: lg/kg/day corresponding target organs in mice and rats The rat thyroid follicular cell tumors and the mammary tumors from two studies (Johnson et al., 1986 and Friedman et al., 1995) were considered of possible relevance for human health Modeling of these data allowed determination of benchmark doses and benchmark dose lower confidence limits (BMDL) For a 10% confidence interval the results were in the range of 300–1100 lg/kg/day for the mammary tumors and between 630 and 930 for the thyroid tumors Shipp et al (2006) used US EPA’s dose-response modeling for determination of a point of departure (POD) for a risk of 10% (lower exposure dose, LED10) Relating the combined tumor data of Johnson and Friedman to Hb adduct data of AA and GA they arrived at 440 or 950 lg/kg/day, respectively Which is close to the BMDLs (see Table 1) Discussion AA is metabolically activated in experimental animals and in humans Adducts of the reactive metabolite GA have been quantitated in DNA and blood proteins in rats and mice, and as pointed out above, adduct formation with Hb has been used as an exposure marker in humans But data on DNA adducts in humans are lacking Since Hb adducts of aromatic amines and serum albumin adducts of aflatoxin B1 have been used in risk assessment of bladder and liver cancer in humans a similar attempt could be made with AA Aromatic amines and aflatoxin show some correspondence of the target tissues in experimental animals and humans In contrast, with AA the target tissues are by no means the same in experimental animals and humans Therefore, an analogous approach cannot be followed It is also tempting to compare Hb adduct data of AA with those of other dietary carcinogens, namely heterocyclic aromatic amines (HAA) in order to estimate their relative mutagenic or carcinogenic potency However, although linear relationships between HAA exposure and DNA adduct formation have been demonstrated in experimental animals (Turteltaub et al., 1990) no information is available about the structural importance of the major adducts at dG-C8 or dG-N2 with respect to mutagenicity, i.e the critical procarcinogenic lesion Since our knowledge on DNA and Hb adducts of AA is even scarcer than for the HAAs it is not possible at the current state of knowledge to draw any conclusions regarding their mutagenic or even carcinogenic potential The only possibility the AA-adduct data provide is in biomonitoring exposure Even in this respect a comparison of AA and HAA is not justified since the metabolism of AA and HAA is vastly differing as is their reaction with macromolecules and the stability of the respective adducts The risk for toxicities of AA have been characterized with respect to their dose-dependent onset or by establishing NOAELs, benchmark dose, and BMDL or calculating a POD (Table 1) Reference doses (RfD) or tolerable daily intakes (TDI) were calculated by applying uncertainty factors which include factors for species extrapolation, variability within the human population, database limitations, and, where appropriate a modifying factor (Shipp et al., 2006) This approach arrives at doses estimates which should be virtually safe for humans even when regularly ingested over a lifetime Another approach was taken by WHO/JECFA (2005) by comparing experimentally derived NOAELs/BMDLs with human exposure levels Thereby a factor is generated which characterizes the margin of exposure (MOE = NOAEL/Exposure, or BMDL/Exposure) from possible toxic effects (Table 1) The RfD/TDI (0.67 lg/kg bw/day) is just in the range of current average dietary exposure However, a NOAEL of 80 lg/kg/day has been estimated for neurotoxicity in humans which is 20-fold higher than current maximal dietary levels In addition, the calculated MOE of 50 for high consumers will be sufficiently protective against neurotoxic effects Also for reproductive effects there is negligible risk The reactivity of AA or its metabolite GA to DNA and protein together with the genotoxicity data and the observed carcinogenicity in rats and mice leads to the conclusion that AA is probably carcinogenic to humans (group 2A, IARC, 1994) The calculated RfD or TDI for cancer risk are not very comfortable as are the respective MOEs, namely for high consumers the range of 75 to 110 lies below the boundaries which are usually applied to carcinogens with a probable genotoxic mechanism of action How shall we deal with the widely distributed AA in food in order to avoid unnecessary additive tumor risk? The precautionary principle should be followed because of insufficient knowledge of the mechanisms involved This 1364 W Parzefall / Food and Chemical Toxicology 46 (2008) 1360–1364 requires that dietary levels of AA be further reduced by appropriate technology in food processing and that AA levels be monitored regularly in commercially distributed food items In contrast, AA levels in home-made food can only be minimized if consumers are instructed and follow appropriate rules of food preparation References Alexander, J., 2006 Risk assessment techniques for acrylamide In: Skog, K., Alexander, J (Eds.), Acrylamide and other hazardous compounds in heat-treated foods CRC Press, Boca Raton, pp 275–295 Ames, B.N., Profet, M., Gold, L.S., 1990 Dietary Pesticides (99.99% all natural) Proc Nat Acad Sci USA 87, 7777–7781 Bergmark, E., 1997 Hemoglobin adducts of acrylamide and acrylonitrile in laboratory workers, smokers and nonsmokers Chem Res Toxicol 10, 78–84 Besaratinia, A., Pfeifer, G.P., 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Chromosomal aberrations in the bone marrow were seen in one mouse strain but not in others, and micronuclei were increased in the bone marrow of mice but not of rats AA is one of the few chemical... glutathione On ground of the metabolites analysed, the authors concluded that the relative internal exposure for glycidamide from dietary acrylamide in humans amounts to only one quarter to one half... consistent association between AA intake and tumorigenesis was found (Pelucchi et al., 2006) In conclusion, none of the epidemiological studies showed convincing contributions of AA to human tumorigenesis