ACRYLAMIDE 17 3. HEALTH EFFECTS 3.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of acrylamide. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not ACRYLAMIDE 18 3. HEALTH EFFECTS the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of acrylamide are indicated in Table 3-4 and Figure 3-2. Because cancer effects could occur at lower exposure levels, Figure 3-2 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 3.2.1 Inhalation Exposure 3.2.1.1 Death Human data are available from two cohort mortality studies of occupational exposure to acrylamide, one by Collins et al. (1989) with most recent follow up by Marsh et al. (2007) and one by Sobel et al. (1986) with follow up by Swaen et al. (2007). In these studies, no significant associations were found between occupational exposure to acrylamide and incidences of death from all causes. See Section 3.1.2.7 (Cancer) for more detailed information regarding these cohorts and assessments of death due to cancers. Reliable information regarding death in animals following inhalation exposure to acrylamide is limited. In a study performed for the American Cyanamid Company (1953a), two dogs, seven rats, and seven guinea pigs (sex and strain unspecified) were exposed to acrylamide dust at 15.6 mg/m3 for 6 hours/day, 5 days/week for up to 12 exposures in a 16-day period. Four of the seven rats died overnight following the first exposure period and two of the remaining rats died a few days later. One of the dogs died on study day 15; there were no deaths among the guinea pigs. The study authors stated that >90% of the particles were in the respirable range (0.3–1.2 μm). ACRYLAMIDE 19 3. HEALTH EFFECTS Reliable inhalation mortality data for each species are recorded in Table 3-1 and plotted in Figure 3-1. 3.2.1.2 Systemic Effects No human or animal data were located regarding cardiovascular, gastrointestinal, musculoskeletal, hepatic, renal, endocrine, or dermal effects following inhalation exposure to acrylamide. Respiratory Effects. Available information regarding acrylamide-associated respiratory effects is restricted to complaints of nose and throat irritation in a group of tunnel workers who had been occupationally exposed to acrylamide and N-methylolacrylamide in a chemical grouting agent for 2 months (Hagmar et al. 2001). Increasing incidences of complaints were associated with increasing levels of hemoglobin adducts of acrylamide. Hematological Effects. No data were located regarding hematological effects in humans following inhalation of acrylamide. Available information in animals is limited to a study in which four rats were exposed to acrylamide as a “saturated” vapor for 6 hours/day, 5 days/week for 3 months at a mean analytical concentration of 1.65 ppm (4.8 mg/m3); the exposures did not affect hematology results (American Cyanamid Company 1954). Ocular Effects. Available information regarding acrylamide-associated ocular effects is restricted to complaints of eye irritation in a group of tunnel workers who had been occupationally exposed to acrylamide and N-methylolacrylamide in a chemical grouting agent for 2 months (Hagmar et al. 2001). Increasing incidences of complaints were associated with increasing levels of hemoglobin adducts of acrylamide. Body Weight Effects. No data were located regarding body weight effects in humans following inhalation of acrylamide. Available information in animals is limited to a study in which four rats were exposed to acrylamide as a “saturated” vapor for 6 hours/day, 5 days/week for 3 months at a mean analytical concentration of 1.65 ppm (4.8 mg/m3); the exposures did not affect body weights (American Cyanamid Company 1954). Table 3-1 Levels of Significant Exposure to Acrylamide - Inhalation ACRYLAMIDE Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m³) (mg/m³) (mg/m³) Chemical Form Comments ACUTE EXPOSURE Death Rat 4 d 1 American Cyanamid Company 6 hr/d 15.6 (death of 4/7 rats in 1 day (NS) and 2 others before day 1953a 8) 15.6 159 Neurological Rat 4 d 2 American Cyanamid Company 6 hr/d 15.6 (loss of coordination and (NS) equilibrium on exposure 1953a day 4) 15.6 166 INTERMEDIATE EXPOSURE 3. HEALTHEFFECTS Death 3 Dog 16 d 15.6 (death of 1/2 dogs on day American Cyanamid Company (NS) 5 d/wk 1953a 6 hr/d 15) 15.6 25 Systemic 4 Cat 3 mo Hemato 4.8 American Cyanamid Company 4.8 5 d/wk 1954 6 hr/d 161 Acrylamide Bd Wt 4.8 4.8 Neurological 5 Gn Pig 16 d 15.6 American Cyanamid Company (NS) 5 d/wk 15.6 1953a 6 hr/d 160 6 Dog 16 d 15.6 (CNS effects including American Cyanamid Company (NS) 5 d/wk 1953a 6 hr/d loss of equilibrium and coordination) 15.6 23 20 Table 3-1 Levels of Significant Exposure to Acrylamide - Inhalation (continued) ACRYLAMIDE Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m³) (mg/m³) (mg/m³) Chemical Form Comments 7 Cat 3 mo 4.8 American Cyanamid Company 5 d/wk 4.8 1954 6 hr/d 82 Acrylamide a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; CNS = central nervous system; d = day(s); Gn pig = guinea pig; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; wk = week(s) 3. HEALTHEFFECTS 21 Figure 3-1 Levels of Significant Exposure to Acrylamide - Inhalation Acute (≤14 days) ACRYLAMIDE cal Death Neurologi mg/m3 100 3. HEALTH EFFECTS 1r 2r 10 c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50 22 d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than q-Cow a-Sheep g-Guinea Pig Cancer Figure 3-1 Levels of Significant Exposure to Acrylamide - Inhalation (Continued) Intermediate (15-364 days) ACRYLAMIDE Systemic al ogic ight ical Death Hematol Body We Neurolog mg/m3 100 3.