HSN: 601

NAME: ACRYLAMIDE

CAS-RN: 79-06-1

DATE: 20180416

Risk Values - Summary Table

Summary Risk Table for:ACRYLAMIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Oral: Non-Cancer
green check
--
--
--
--
--
--
--
--
green check
Oral: Cancer
green check
--
green check
--
--
green check
--
--
--
green check
Inhalation: Non-Cancer
green check
--
--
--
--
--
--
--
--
green check
Inhalation: Cancer
green check
--
green check
--
--
--
--
--
--
green check
green check = Chemical evaluated and ITER data online.


Noncancer Oral Risk Values Table:

ITER Noncancer Oral Risk Table for: ACRYLAMIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value Namechronic MRL
--
--
--
--
--
--
--
--
RfD
Risk Value*1E-3
--
--
--
--
--
--
--
--
2E-3
Year2012
--
--
--
--
--
--
--
--
2010
Base(Experimental)*BMDL05 0.18
--
--
--
--
--
--
--
--
BMDL5 0.27
Basis(Adjusted)*HEDBMDL05 0.042
--
--
--
--
--
--
--
--
HEDBMDL 0.053
Uncertainty Factor30
--
--
--
--
--
--
--
--
30
Critical Organ or Effectnervous system
--
--
--
--
--
--
--
--
nervous system
Speciesrat
--
--
--
--
--
--
--
--
rat
StudyFriedman et al., 1995
--
--
--
--
--
--
--
--
Johnson et al., 1986
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
--
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
--
--
--
--
--
--
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Noncancer Oral Synopsis:

ATSDR and U.S. EPA have evaluated the noncancer oral toxicity data for acrylamide. EPA derived a reference dose (RfD) of 0.002 mg/kg-day based on the observation of nerve damage in rats exposed to acrylamide in drinking water for 2 years (Johnson et al., 1986). EPA's point of departure was based on benchmark dose (BMD) modeling of incidence data for microscopically-detected degenerative nerve changes in male F344 rats, resulting in a BMDL5 of 0.27 mg/kg-day. Data on the relationships between hemoglobin (Hb) adducts, serum levels, and administered dose as reported in a number of studies in rats and humans were used to estimate the internal dose in rats, to extrapolate that dose to an internal dose in humans, and then to estimate the daily human intake of acrylamide needed to produce that internal human dose comparable to what would be produced in rats at the point-of-departure. These extrapolations resulted in a conversion factor of 140.1 uM acrylamide-hr per mg acrylamide/kg bw that was used to derive the HEDBMDL0.053 mg/kg-day from the rat BMDL. EPA applied a composite uncertainty factor of 30 (3 to account for uncertainties in extrapolating from rats to humans for toxicodynamic differences and 10 for human variability).

ATSDR derived a chronic oral minimal risk level (MRL) of 0.001 mg/kg-day based on a BMD-predicted rat blood TWA acrylamide-based BMDL05 of 0.00024 mM (corresponding to a rat external dose of 0.18 mg/kg-day) for degenerative sciatic nerve changes in male F344 rats administered acrylamide in the drinking water for up to 2 years (Friedman et al., 1995). A human PBPK model (Sweeney et al., 2010) was used to predict the daily HED of 0.042 mg/kg-day corresponding to the BMDL05 value for PBPK model-predicted rat blood TWA acrylamide dose from the best-fitting model. ATSDR applied a composite uncertainty factor of 30 (3 for extrapolation from animals to humans using dosimetric adjustment and 10 for human variability).

Noncancer Oral Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

BIB:
Friedman MA, Dulak LH, Stedham MA. 1995. A lifetime oncogenicity study in rats with acrylamide. Fundam Appl Toxicol 27(1):95-105.

Sweeney LM, Kirman CR, Gargas ML, et al. 2010. Development of a physiologically-based toxicokinetic model of acrylamide and glycidamide in rats and humans. Food Chem Toxicol 48(2):668-685.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2012. Toxicological Profile for Acrylamide. U.S. Department of Health and Human Services, Public Health Service. December. Available at http://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=1112&;tid=236

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html

Noncancer Oral Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Acrylamide (U.S. EPA, 2010).

BIB:
Johnson, K.A., S.J. Gorzinski, K.M. Bodner, R.A. Campbell, C.H. Wolf, M. A. Friedman, R.W. Mast. 1986. Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicol. Appl. Pharmacol. 85: 154-168.

U.S. EPA. 2010. Toxicological Review of Acrylamide (CAS No. 79-06-1). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-07/009F. Available at http://www.epa.gov/iris/toxreviews/0286tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0286.htm


Cancer Oral Risk Values Table:

ITER Cancer Oral Risk Table for: ACRYLAMIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value NameNA
--
NA
--
--
RSD
--
--
--
RSD
Risk Value*NA
--
NA
--
--
3E-4
--
--
--
2E-5
Year2012
--
1994
--
--
2008
--
--
--
2010
ClassificationNA
--
2A
--
--
NA
--
--
--
see below
Target OrganNA
--
NA
--
--
thyroid
--
--
--
multiple
SpeciesNA
--
NA
--
--
rat
--
--
--
rat
StudyNA
--
NA
--
--
Johnson et al., 1986; Friedman et al., 1995
--
--
--
Johnson et al., 1986
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
--
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
Click here
--
--
Click here
--
--
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Cancer Oral Synopsis:

ATSDR, IARC, U.S. EPA, and Dourson et al. (2008) (under ITER PR column) have evaluated the oral carcinogenicity data for acrylamide. IARC classified acrylamide as probably carcinogenic to humans (Group 2A), based on inadequate evidence for carcinogenicity to humans and sufficient evidence for carcinogenicity to animals. In making the overall evaluation, the Working Group took into consideration the following supporting evidence: (i) Acrylamide and its metabolite glycidamide form covalent adducts with DNA in mice and rats. (ii) Acrylamide and glycidamide form covalent adducts with haemoglobin in exposed humans and rats. (iii) Acrylamide induces gene mutations and chromosomal aberrations in germ cells of mice and chromosomal aberrations in germ cells of rats and forms covalent adducts with protamines in germ cells of mice in vivo. (iv) Acrylamide induces chromosomal aberrations in somatic cells of rodents in vivo. (v) Acrylamide induces gene mutations and chromosomal aberrations in cultured cells in vitro. (vi) Acrylamide induces cell transformation in mouse cell lines. The IARC evaluation considers the evidence of carcinogenicity in humans and experimental animals, as well as other data relevant to the evaluation of carcinogenicity and its mechanisms. IARC does not generally develop risk values or other estimates of potency.

In accordance with the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), EPA characterized acrylamide as "likely to be carcinogenic to humans" based on the observation of increased incidences of thyroid follicular cell tumors, scrotal sac mesotheliomas, and mammary gland fibroadenomas in rats following chronic oral exposure to acrylamide in drinking water. In addition, acrylamide initiated skin tumors and induced lung adenomas in mice, and is genotoxic in mammalian cells. EPA derived an oral slope factor of 0.5 per (mg/kg-day) based on the summed risks for increased incidence of thyroid tumors and tunica vaginalis mesotheliomas in male F344 rats exposed to acrylamide in drinking water for 2 years (Johnson et al., 1986). EPA used the area under the curve (AUC) for glycidamide as the dose metric to derive the oral slope factor. Glycidamide is considered to be the putative toxin leading to carcinogenicity, and thus, is a better internal dose metric to correlate to response than the internal (or external) level of acrylamide. TERA converted the EPA slope factor to a dose at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the slope factor of 5E-1 per (mg/kg)-day to determine a risk specific dose (RSD) of 0.00002 mg/kg-day.

In accordance with U.S. EPA (2005) guidelines, Dourson et al. (2008) (under the ITER column) determined that tumors from acrylamide exposure were evoked by two MOAs, genotoxicity and growth stimulation, and derived a cancer slope factor of 0.030 (mg/kg-day) by pooling the incidence data for thyroid tumors in male and female rats exposed to acrylamide in drinking water for two years (Johnson et al. 1986, Friedman et al 1995). Dourson et al. used the probit model to analyze the thyroid tumor data and used the area under the curve for glycidamide as the dose metric to derive the oral slope factor. TERA converted the Dourson et al. slope factor to a dose at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the slope factor of 3E-2 per (mg/kg)-day to determine a risk specific dose (RSD) of 0.0003 mg/kg-day.

Although EPA and Dourson et al. considered data from the same studies in developing oral slope factors, and made similar judgments on the MOAs (in part), the organizations made different choices that resulted in different values. EPA summed the risks associated with increased incidence of thyroid tumors and tunica vaginalis mesotheliomas in male rats from a single study while Dourson et al. pooled thyroid tumor incidence data from four data sets (male and female rats in two different drinking water studies). The organizations selected different models to generate the point of departure (POD). EPA used the multistage model with a default 10\% benchmark response while Dourson et al. used the probit model with 2\% benchmark response.

ATSDR has published a Toxicological Profile for Acrylamide. Although ATSDR discusses the carcinogenicity data in its Toxicological Profiles, it does not assess cancer potency or perform cancer risk assessments.

Cancer Oral Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2012. Toxicological Profile for Acrylamide. U.S. Department of Health and Human Services, Public Health Service. December. Available at http://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=1112&;tid=236

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html

Cancer Oral Specifics:

IARC

PEER:
Each IARC evaluation is developed by an international working group of experts, which meets to discuss and finalize the monograph text and to formulate the evaluations. Working Group members are chosen on the basis of their knowledge and experience, with due regard given to avoid situations where financial or other interests might affect the outcome of their work. The members of a Working Group are invited to serve in their individual capacities as scientists, and not as representatives of their governments or of any organization with which they are affiliated. Representatives of national and international agencies are also invited to the meetings, and others may attend as observers.

MOREI:
International Agency for Research on Cancer (IARC) Monographs. Some Industrial Chemicals. 1994. Volume 60, page 425. Summaries &; Evaluations available at http://monographs.iarc.fr/ENG/Monographs/vol60/index.php

Additional information about the IARC Monographs (including ordering information and links to other Monographs) can be found at http://monographs.iarc.fr/

Cancer Oral Specifics:

ITER PR

PHC:
Four long-term experiments in rats were relevant for the assessment of potential risk in humans, and showed that acrylamide can cause tumors. Johnson et al. (1986) published results for two experiments, one in male and one in female rats. Friedman et al. (1995) also published results for two experiments, one in male and one in female rats, using the same strain of rats. Thyroid tumors in rats exposed to acrylamide were observed to be statistically significant in all four experiments; three of these significances were confirmed by a Fisher exact test. Although, scientists have not identified any chemical that has caused thyroid tumors in humans and the rat thyroid is different from the human thyroid in ways that may be significant, conservative risk assessments use these rat tumors unless data suggest otherwise. Therefore, Dourson et al. (2008) considered that these tumors are relevant to humans. The type of thyroid tumors formed in rats is generally recognized as resulting from growth stimulation and/or mutation, and these modes of action also operate in humans.

The critical studies also observed increased incidence of mammary tumors and tunica vaginalis mesotheliomas; however, these tumor types were considered to be less relevant to humans than the thyroid tumors for several reasons. Up to four different kinds of mammary tumors were observed in two of the four experiments, three of these tumors were statistically significantly observed, one of these significances was confirmed by a Fishers exact test. The statistically significant tumors only occurred in females, and tumors developed were not consistent among experiments. In addition, Friedman et al., (1995) questioned the relevance of their experiment's control animals in comparison to historical controls. Multiple modes of action are likely to be occurring with these inconsistently observed mammary tumors and not all of these modes of action are likely to be relevant to humans. Therefore, Dourson et al. (2008) concluded that these mammary tumors were neither consistent nor fully relevant to humans (see also Maier et al., 2010). Similar to U.S. EPA (2010), Dourson et al. (2008) did not consider tumors of the adrenal gland, central nervous system, clitoral gland, oral tissues, pituitary gland, and uterus to be sufficiently consistent among the rat experiments, and/or relevant to humans for a more comprehensive dose-response assessment. Tumors of the tunica vaginalis were also not considered relevant and the reasoning for discounting these tumors is further explained by Haber et al. (2009).

Acrylamide is genotoxic, but not directly mutagenic. A principal metabolite of acrylamide, glycidamide, is mutagenic. Acrylamide also causes growth stimulation and oxidative stress, the latter of which can lead to mutations and other genotoxicity. Mutagenicity and genotoxicity from acrylamide exposure have only been seen at doses higher than those that caused tumors in the four experiments mentioned above. Furthermore, tumors precede genotoxicity in the dose scale, and the shapes of dose-response curves for tumors and mutagenicity and genotoxicity are generally much different. Accordingly, it is unlikely that the tumors evoked are solely caused by either mutagenicity or genotoxicity. Unmeasured mutagenicity might be occurring at low doses and might be responsible for some of the low dose tumors. In fact, mutagenicity appears to lead low-dose only tumors. The weight of scientific evidence supports growth stimulation as contributing to thyroid tumors. Specifically:

-Khan et al. (1999) showed statistically significant morphological changes in the thyroid consistent with stimulation after acrylamide for 2 or 7 days.

-Lafferty et al. (2004) observed three measures of growth stimulation in the thyroid after acrylamide for 7, 14 &; 28 days; DNA labeling was statistically significant by pairwise comparison. Chico-Galdo et al. (2006) results suggest that DNA labeling in Lafferty et al. (2004) was growth stimulation.

-Friedman et al. (1999) showed thyroid hormones to be statistically significantly decreased in males after 28 days of exposure (trend test &; pairwise comparison). Females appeared to be affected, but less so.

-Johnson et al. (1986) showed thyroid hyperplasia in both male and female rats after 2 years of exposure (statistically significantly-trend test).

Comparison with U.S. EPA (1998) examples also supports this mode of action for acrylamide. Tumors evoked by acrylamide exposure were generally benign, occurred late in life, and were more often in hormonally-active organs, in all four experiments. Such tumor appearance is more consistent with manners of tumor formation that are different from direct mutation. These observations also mean it is unlikely that direct mutations are causing all of the tumors in these experiments. Thus, both a mutagenic and non-mutagenic manners of tumor formation are likely to contribute to thyroid tumors.

QEST:
U.S. EPA (2005) suggests "decoupling" data when several modes of action occur in different parts of the dose response curve. Thus, Dourson et al (2008) concluded that a mutagenic, non-threshold, linear mode of action may be occurring at doses of less than 1 mg/kg-day, and a growth stimulation, threshold, non-linear mode of action likely dominates at doses in excess of 1 mg/kg-day. U.S. EPA (2005) suggests that selection of a point of departure be close to the lower range of data of interest. Pooling thyroid tumors over 19 dose groups show that 2\% extra risk is approximately double the background rate of the pooled data, and 1/3 of the highest low dose response rate of ~6\%. Therefore, Dourson et al. (2008) concluded that a 2\% BMR is comfortably within the interpolation range allowing for a stable estimate for the point of departure. Using U. S. EPA (2005) guidelines, Dourson et al. (2008) compared different mathematical models in an attempt to fit these "decoupled" data and concluded that the Multistage model did not fit "decoupled" data well. The Weibull model fit these "decoupled" data well with fixed power of 2, but U.S. EPA software did not allow a positive value for control doses with power unfixed; controls animals had a positive dose. The Probit model fit these "decoupled" data well, showing a linear response for tumors in the low dose range and a curvilinear upward trend for tumors from growth stimulation in the high dose range. When low dose "decoupled" data only were considered, a weighted linear regression and a multistage model both confirmed the use of the probit model to generate a point of departure for the low dose extrapolation.

The probit model Benchmark dose (BMD) of 2\% extra risk is 0.81 mg/kg-day, which is associated with a slope of 0.025 (mg/kg-day)-1. Slope value adjusted by 1.2 for known kinetic rat and human differences; not further adjusted for dynamic variability because Williams (1995) states that thyroid tumors in humans do not form in the presence of mutagens if TSH-stimulated growth is prevented; U.S. EPA (1998) considers an adjustment factor of 1 for chemicals having a growth stimulation mode of action, unless specific data suggest otherwise; Allen et al. (1988) showed in published studies of human and animal tumor slope factors that the most likely value for an overall factor is roughly 1-fold; Goodman and Wilson (1991) consider the best estimate of the interspecies factor to be log normally distributed around a value of 1. The adjusted slope factor is 0.030 (mg/kg-day)-1.

In the low end of the dose range, a mutagenic MOA has some supporting and detracting data; in the high end of the dose range, a thyroid growth stimulation MOA has more supporting and less detracting data. While neither set of supporting or detracting data for either MOA is definitive, both sets of data are consistent with a biphasic or "decoupled" approach described in U.S. EPA (2005) guidelines. Therefore, based on the best evidence available, we determine a slope factor (SF) of 0.030 (mg/kg-day)-1 for the linear, low dose, part of the dose-response curve [upper bound estimate of 0.035 (mg/kg-day)-1], with an RfD of 0.02 to 0.05 mg/kg-day for the portion of the dose-response driven by growth stimulation, a non-linear, high dose effect. The SF can be used to determine risks associated with exposure to acrylamide at doses less than 0.02 mg/kg-day. The RfD of 0.02 mg/kg-day can be used to assess risks posed by acrylamide doses between 0.02 and 0.05 mg/kg-day. Should it be necessary, risks associated with exposures to doses greater than 0.05 mg/kg-day can be determined by reference to the probit model described in Dourson et al. (2008). Together, this SF and RfD define lower and upper bounds on exposures of concern for subsequent risk management decisions, consistent with the guidance of EPA (1998) when both linear and non-linear techniques are used in the dose response assessment.

The review panel comments and conclusions are as follows:

The panel agreed that there are multiple modes of action for the thyroid tumors in rats caused by acrylamide, but the relevance of these thyroid tumors to humans was questioned because there are known problems extrapolating from rat to human thyroid (physiologically). Rats may not be an adequate predictor of humans, with estimations of human risk from rats erring on the side of conservatism.

The panel agreed that two different modes of action cause the dose-response curve to have different slopes in the low and high dose regions. Mutagenicity appears to dominate in the low dose region and stimulation of growth appears to dominate in the high dose region. Although the panel agreed with the "decoupling" of the data as suggested by U.S. EPA (2005), it saw the effects more working together to evoke the overall tumor response.

As part of the dose-response assessment, the authors modeled control groups at a 0.002 mg/kg-day dose level because acrylamide was found in rat chow at this level. The panel suspected that this did not result in much change to the estimated risk and requested the authors re-run their model using control groups at a zero dose, rather than the 0.002 mg/kg-day. The authors reported that setting control values to zero was only influential in the estimation of a slope value at the 4th digit of precision, indicating very little influence on the outcome from a risk assessment point of view. The authors were not able to run the log-dose-probit model with the controls at zero dose because of the inability of the model to show zero doses on the log-dose scale.

The authors explored several models for the dose-response assessment, including the multistage, probit, and Weibull model, the latter of which U.S. EPA (1998) recommends for thyroid tumors. The Weibull and probit models yielded similar results; both of these model results were confirmed by a linear regression on low dose tumors only. The multistage model did not fit the overall data as well. The panel requested that a table or figure comparing the models be provided as supplemental information on ITER. In response to the panel's request, these tables and figures can be found in Appendix C of the ITER Review Meeting Report at http://www.tera.org/Peer/ITERReview/ITER\%20Review\%20Meeting\%201\%20Final\%20Report.pdf

The panel considered that the risk assessment methodology used was appropriate, especially since it was based on U.S. EPA (2005) and used U.S. EPA BMD software, but while the guidelines recommend decoupling the data given competing MOAs, this has not been applied routinely in previous risk assessments. The panel was concerned that some ITER users would find it difficult to fully evaluate the complexities of this assessment and suggested the authors provide additional explanation to enhance transparency and understanding. Specifically, the panel asked the authors to explain how the ITER user can interpret this cancer value and compare with other available values, describe the range of margins of exposure for the risk specific dose, and clarify the purpose of the reference dose found in Dourson et al. (2008) and how it might be used. The authors requested additional information so that users do not misuse this value, and it is fully explained when users should choose the cancer slope value over the RfD. For example, the authors could mention that the slope factor is applicable for low dose extrapolation, but that due to multiple modes of action and other effects taking over at higher dose range. The authors need to specify this range.

PEER:
The risk value for acrylamide derived by Dourson et al. (2008) underwent journal peer review prior to publication. To be included on ITER, it has also undergone a brief additional review by a panel of independent volunteer experts convened by Toxicology Excellence for Risk Assessment (TERA) on February 15-16, 2011, in Cincinnati, OH. The panel members included: Dr. John Christopher, CH2M/Hill, Inc.; Dr. Terresa Nusair, The Health &; Environmental Safety Alliance, Inc. (HESA); and Dr. Glenn Talaska, The University of Cincinnati.

The purpose of this panel review was to evaluate whether the acrylamide risk value was derived using acceptable methodology, whether the methodology was applied correctly, and if the resulting risk value would be of value to ITER users. The panel reviewed and approved this toxicity value for acceptance onto ITER; and panel comments and conclusions are included in the quantitative estimate section. However, the panel was not asked to explicitly endorse the value derived by Dourson et al. (2008). The ITER Review Meeting Report (including panel comments, conclusions, and supplemental information requested by the panel) is available at http://www.tera.org/Peer/ITERReview/ITER\%20Review\%20Meeting\%201\%20Final\%20Report.pdf

BIB:
Allen, B.C., Crump, K.S., Shipp, A.M., 1988. Correlation between carcinogenic potency of chemicals in animals and humans. Risk Anal. 8, 531-544.

Chico Galdo, V., Massart, C., Jin, L., Vanvooren, V., Caillet-Fauquet, P., Andry, G., Lothaire, P., Dequanter, D., Friedman, M. and J. Van Sande. 2006. Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures. Molecular and Cellular Endocrinology: 257-258:6-14.

Friedman, M. A., Dulak, L. H., Keefe R.T., et al., 1999. Effects of Acrylamide on Rat Hormone Levels in a 28-Day Drinking Water Study. Toxicol. Appl. Pharmacol.

Friedman, M. A., Dulak, L. H., Stedham, M. A., 1995. A lifetime oncogenicity study in rats with acrylamide. Fundam. Appl. Toxicol. 27, 95-105.

Goodman, G., Wilson, R., 1991. Predicting the carcinogenicity of chemicals in humans from rodent bioassay data. Environ. Health Perspect. 94, 195-218.

Haber, L.T., A. Maier, O.L. Kroner, and M.J. Kohrman. 2009. Assessment of Human Relevance and Mode of Action for Tunica Vaginalis Mesotheliomas Resulting from Oral Exposure to Acrylamide. Regul. Toxicol. Pharmacol. 53(2): 134-149. Available at http://www.tera.org/Publications/Haber\%20et\%20al.\%202009.pdf

Johnson, K. A., Gorzinski, S. J., Bodner, K. M., Campbell, R. A., Wolf, C. H., Friedman, M. A., Mast, R. W., 1986. Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicol. Appl. Pharmacol. 85, 154-68.

Khan, M. A., Davis, C. A., Foley, G. L., Friedman, M. A., Hansen, L. G., 1999. Changes in thyroid gland morphology after acute acrylamide exposure. Toxicol. Sci. 47, 151-7.

Lafferty, J. S., Kamendulis, L. M., Kaster, J., Jiang, J., Klaunig, J. E., 2004. Subchronic acrylamide treatment induces a tissue-specific increase in DNA synthesis in the rat. Toxicol. Lett. 154, 95-103.

Maier, A., M. Kohrman-Vincent, R. Hertzberg, B. Allen, L.T. Haber, M.L. Dourson, M.L. 2010. Re-evaluation of Dose-Response Options for F344 Rat Mammary Tumors for Acrylamide - Additional Insights Based on Mode of Action. Food Chem Toxicol. Submitted.

U.S. EPA (Environmental Protection Agency). 1998. Assessment of thyroid follicular cell tumors. Risk Assessment Forum. Washington, DC. U.S. Environmental Protection Agency. EPA/630/R-97/002. March.

U.S. EPA (Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Available at http://www.epa.gov/cancerguidelines/

Williams, E., 1995. Mechanisms and pathogenesis of thyroid cancer in animals and man. Mutat. Res. 333, 123-129.

MOREI:
Dourson M., Hertzberg R., Allen B., Haber L., Parker A., Kroner O., Maier A., Kohrman M. 2008. Evidence-Based Dose-Response Assessment for Thyroid Tumorigenesis from Acrylamide. Reg. Toxicol. Pharmacol. 52: 264-289. Available at http://www.ncbi.nlm.nih.gov/pubmed/18775759

Cancer Oral Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Acrylamide (U.S. EPA, 2010).

BIB:
Johnson, K.A., S.J. Gorzinski, K.M. Bodner, R.A. Campbell, C.H. Wolf, M. A. Friedman, R.W. Mast. 1986. Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicol. Appl. Pharmacol. 85: 154-168.

U.S. EPA. 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Available at http://www.epa.gov/cancerguidelines/

U.S. EPA. 2010. Toxicological Review of Acrylamide (CAS No. 79-06-1). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-07/009F. Available at http://www.epa.gov/iris/toxreviews/0286tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0286.htm


Noncancer Inhalation Risk Values Table:

ITER Noncancer Inhalation Risk Table for: ACRYLAMIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value Namechronic MRL
--
--
--
--
--
--
--
--
RfC
Risk Value*NA
--
--
--
--
--
--
--
--
6E-3
Year2012
--
--
--
--
--
--
--
--
2010
Base(Experimental)*NA
--
--
--
--
--
--
--
--
HEDBMDL 0.053
Basis(Adjusted)*NA
--
--
--
--
--
--
--
--
HECBMDL 0.18
Uncertainty FactorNA
--
--
--
--
--
--
--
--
30
Critical Organ or EffectNA
--
--
--
--
--
--
--
--
nervous system
SpeciesNA
--
--
--
--
--
--
--
--
rat
StudyNA
--
--
--
--
--
--
--
--
Johnson et al., 1986
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
--
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
--
--
--
--
--
--
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Noncancer Inhalation Synopsis:

ATSDR and U.S.EPA evaluated the noncancer inhalation toxicity data for acrylamide. EPA derived a reference concentration (RfC) of 0.006 mg/m3 using a route-to-route extrapolation from the HEDBMDL of 0.053 mg/kg-day that was based on the degenerative nerve changes observed in the Johnson et al. (1986) oral exposure study. The HECBMDL of 0.18 mg/m3 was calculated from the HEDBMDL based on a 70 kg person who breathes 20 m3 of air daily. EPA applied a total uncertainty factor of 30 (10 to account for inter-individual variability in toxicokinetics and toxicodynamics to protect potentially sensitive populations and lifestages and 3 to account for uncertainties in extrapolating from rats to humans for toxicodynamic differences). ATSDR did not derive any inhalation minimal risk levels (MRLs) for acrylamide because appropriate data were not identified to establish concentration-response relationships.

Noncancer Inhalation Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2012. Toxicological Profile for Acrylamide. U.S. Department of Health and Human Services, Public Health Service. December. Available at http://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=1112&;tid=236

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html

Noncancer Inhalation Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Acrylamide (U.S. EPA, 2010).

BIB:
Johnson, K.A., S.J. Gorzinski, K.M. Bodner, R.A. Campbell, C.H. Wolf, M. A. Friedman, R.W. Mast. 1986. Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicol. Appl. Pharmacol. 85: 154-168.

U.S. EPA. 2010. Toxicological Review of Acrylamide (CAS No. 79-06-1). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-07/009F. Available at http://www.epa.gov/iris/toxreviews/0286tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0286.htm


Cancer Inhalation Risk Values Table:

ITER Cancer Inhalation Risk Table for: ACRYLAMIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value NameNA
--
NA
--
--
--
--
--
--
RSC
Risk Value*NA
--
NA
--
--
--
--
--
--
1E-4
Year2012
--
1994
--
--
--
--
--
--
2010
ClassificationNA
--
2A
--
--
--
--
--
--
see below
Target OrganNA
--
NA
--
--
--
--
--
--
multiple
SpeciesNA
--
NA
--
--
--
--
--
--
rat
StudyNA
--
NA
--
--
--
--
--
--
Johnson et al., 1986
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
--
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
Click here
--
--
--
--
--
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Cancer Inhalation Synopsis:

ATSDR, IARC, and U.S. EPA evaluated the carcinogenicity data for acrylamide. In accordance with the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), EPA characterized acrylamide as "likely to be carcinogenic to humans" based on the observation of increased incidences of thyroid follicular cell tumors, scrotal sac mesotheliomas, and mammary gland fibroadenomas in rats following chronic oral exposure to acrylamide in drinking water. In addition, acrylamide initiated skin tumors and induced lung adenomas in mice, and is genotoxic in mammalian cells. EPA determined that no human or animal inhalation cancer dose-response data were available for acrylamide to directly derive an inhalation unit risk. Therefore, EPA derived an inhalation unit risk using a route-to-route extrapolation (oral-to-inhalation exposure) by converting the oral HEDBMDL from the Johnson et al. (1986) study to a human equivalent air concentration (HEC). EPA assumed a continuous 24-hour inhalation exposure for a 70 kg person who breathes 20 m3/day air. The resulting inhalation unit risk is 1 E-4 per (ug/m3). TERA converted the EPA inhalation unit risk estimate to a concentration at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the inhalation unit risk of 1E-4 per (ug/m3) (and then by another 1000 to convert to mg/m3) to determine a risk specific concentration (RSC) of 0.0001 mg/m3.

IARC classified acrylamide as probably carcinogenic to humans (Group 2A), based on inadequate evidence for carcinogenicity to humans and sufficient evidence for carcinogenicity to animals. In making the overall evaluation, the Working Group took into consideration the following supporting evidence: (i) Acrylamide and its metabolite glycidamide form covalent adducts with DNA in mice and rats. (ii) Acrylamide and glycidamide form covalent adducts with haemoglobin in exposed humans and rats. (iii) Acrylamide induces gene mutations and chromosomal aberrations in germ cells of mice and chromosomal aberrations in germ cells of rats and forms covalent adducts with protamines in germ cells of mice in vivo. (iv) Acrylamide induces chromosomal aberrations in somatic cells of rodents in vivo. (v) Acrylamide induces gene mutations and chromosomal aberrations in cultured cells in vitro. (vi) Acrylamide induces cell transformation in mouse cell lines. The IARC evaluation considers the evidence of carcinogenicity in humans and experimental animals, as well as other data relevant to the evaluation of carcinogenicity and its mechanisms. IARC does not generally develop risk values or other estimates of potency.

ATSDR has published a Toxicological Profile for Acrylamide. Although ATSDR discusses the carcinogenicity data in its Toxicological Profiles, it does not assess cancer potency or perform cancer risk assessments.

Cancer Inhalation Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2012. Toxicological Profile for Acrylamide. U.S. Department of Health and Human Services, Public Health Service. December. Available at http://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=1112&;tid=236

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html

Cancer Inhalation Specifics:

IARC

PEER:
Each IARC evaluation is developed by an international working group of experts, which meets to discuss and finalize the monograph text and to formulate the evaluations. Working Group members are chosen on the basis of their knowledge and experience, with due regard given to avoid situations where financial or other interests might affect the outcome of their work. The members of a Working Group are invited to serve in their individual capacities as scientists, and not as representatives of their governments or of any organization with which they are affiliated. Representatives of national and international agencies are also invited to the meetings, and others may attend as observers.

MOREI:
International Agency for Research on Cancer (IARC) Monographs. Some Industrial Chemicals. 1994. Volume 60, page 425. Summaries &; Evaluations available at http://monographs.iarc.fr/ENG/Monographs/vol60/index.php

Additional information about the IARC Monographs (including ordering information and links to other Monographs) can be found at http://monographs.iarc.fr/

Cancer Inhalation Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Acrylamide (U.S. EPA, 2010).

BIB:
Johnson, K.A., S.J. Gorzinski, K.M. Bodner, R.A. Campbell, C.H. Wolf, M. A. Friedman, R.W. Mast. 1986. Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. Toxicol. Appl. Pharmacol. 85: 154-168.

U.S. EPA. 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Available at http://www.epa.gov/cancerguidelines/

U.S. EPA. 2010. Toxicological Review of Acrylamide (CAS No. 79-06-1). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-07/009F. Available at http://www.epa.gov/iris/toxreviews/0286tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0286.htm

NO Revision History: