PERCHLORATES 27 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 perchlorates. 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. The perchlorate anion forms salts with a wide variety of cations. There are five perchlorate salts that are manufactured in substantial amounts: magnesium, potassium, ammonium, sodium, and lithium perchlorate (see Section 4.1). The potassium, sodium, and ammonium salts are the ones most commonly encountered in the toxicology literature. Therefore, data on potassium, sodium, ammonium, and other perchlorate salts were considered pertinent to the assessment of the perchlorate anion. Perchloric acid was not included because it is a strong acid and its toxicity is dominated by the irritating effects of the hydrogen cation. In the absence of water, the five commercial perchlorates listed above will exist as a solid. In water, perchlorate salts (perchlorates) will rapidly dissolve and completely dissociate into the perchlorate anion, also referred to as perchlorate, and the corresponding metal cation. Potassium, ammonium, and sodium cations are ubiquitous in the environment and are considered spectator ions. Therefore, the species of concern in this document is the perchlorate anion. 3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others address the needs of persons potentially exposed to perchlorate, 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 PERCHLORATES 28 3. HEALTH EFFECTS 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 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. 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 No studies were located regarding lethality in humans or animals after inhalation exposure to perchlorate. 3.2.1.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, dermal, or ocular effects in humans or animals after inhalation exposure to perchlorate. PERCHLORATES 29 3. HEALTH EFFECTS The highest NOAEL values for systemic effects from the two occupational studies available are recorded in Table 3-1 and plotted in Figure 3-1. Hematological Effects. No hematological effects were found in ammonium perchlorate workers (22–31 high-dose and 18–27 low-dose versus 72–150 controls) exposed for 1–27 years (mean=8.3 years) to average perchlorate concentrations of up to 0.63 mg/m3 (Gibbs et al. 1998). The researchers estimated an average cumulative lifetime perchlorate absorbed dose of 38 mg/kg in the high-dose workers in this study, which corresponds to a daily dose of 0.01 mg/kg/day based on the approximate average exposure duration of 9 years for high-dose workers. Oral exposure due to deposition in the mouth and throat was also likely to have occurred. The accuracy of dose estimates from this study is questionable; however, because the researchers estimated the fraction absorbed using a study on an unrelated chemical and did not consider the size of the inhaled ammonium particles in their calculations. Particle size (mean and distribution) is an important determinant of inhaled dose for particulates (EPA 1994). A similar study of 37 ammonium perchlorate workers also found no evidence of hematological effects among the workers (Lamm et al. 1999). The workers were assigned to one of three categories of presumptive exposure based on visible dust generated. The average airborne exposure for the high-exposure group was 8.6 mg/day (respirable fraction; particle size 0.1–10 μm) or 59.4 mg/day (total particulate perchlorate). Dividing by the default inhalation volume of 10 m3/day results in a respirable concentration of 0.86 mg/m3. The absorbed oral dose per shift was calculated using urinary perchlorate measurements and the assumption that the absorbed dose that is excreted is 95%. In the low-, medium-, and high-exposure categories, the absorbed doses were estimated to be 4, 11, and 34 mg perchlorate/day, respectively. Assuming a body weight of 70 kg, the 34 mg/kg oral dose corresponds to about 0.5 mg perchlorate/kg/day. Measures of cumulative exposure were not considered in this study. It should be noted that workers exposed to perchlorate have an unusual work schedule consisting of three 12-hour day shifts followed by 3 days unexposed. No studies were located regarding hematological effects in animals after inhalation exposure to perchlorate. Hepatic Effects. No effects on serum enzymes indicative of liver toxicity were found in the ammonium perchlorate workers studied by Gibbs et al. (1998) or among those studied by Lamm et al. (1999) (see Hematological Effects above for further details on these studies). No further relevant information was located. Table 3-1 Levels of Significant Exposure to Perchlorates - Inhalation PERCHLORATES 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 CHRONIC EXPOSURE Systemic 1 Human 1-27 yr Hemato 0.63 Gibbs et al. 1998 (avg=8.3 yr) 0.63 (occup) NH4ClO4 126 Hepatic 0.63 0.63 Renal 0.63 0.63 Endocr 0.63 0.63 2 Human 40% over 5 yr Hemato 0.86 Lamm et al. 1999 0.86 (occup) 3. HEALTHEFFECTS 211 NH4ClO4 Hepatic 0.86 0.86 Renal 0.86 0.86 Endocr 0.86 0.86 a The number corresponds to entries in Figure 3-1. avg = average; Endocr = endocrine; Hemato = hematological; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; occup = occupational; yr = year(s) 30 Figure 3-1. Levels of Significant Exposure to Perchlorates - Inhalation Chronic (≤365 days) PERCHLORATES Systemic l ca gi lo ne to ic ri a at al oc em ep en d mg/m3 H H R E n 1 2 2 2 2 1 1 1 1 3. HEALTH EFFECTS 0.1 c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50 31 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 PERCHLORATES 32 3. HEALTH EFFECTS No studies were located regarding hepatic effects in animals after inhalation exposure to perchlorate. Renal Effects. No effects on serum enzymes indicative of kidney toxicity or in serum creatinine and blood urea nitrogen (BUN) were found in the ammonium perchlorate workers evaluated by Gibbs et al. (1998) or Lamm et al. (1999) (see Hematological Effects above for further details on these studies). No studies were located regarding renal effects in animals after inhalation exposure to perchlorate. Endocrine Effects. No significant effects on serum levels of TSH, total serum thyroxine (TT4), T3, or free thyroxine index (FTI) were found among the ammonium perchlorate workers studied by Gibbs et al.