TRICHLOROETHYLENE 23 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 trichloroethylene. 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 (e.g., death, systemic, immunological, neurological, reproductive, developmental, 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 TRICHLOROETHYLENE 24 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 trichloroethylene are indicated in Tables 3-1 and 3-3 and Figures 3-1 and 3-17. 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 Humans have died from breathing high concentrations of trichloroethylene fumes. Most of the reported deaths have been associated with accidental breathing of unusually high levels of trichloroethylene vapors in the workplace during its use in cleaning, degreasing, dry cleaning, or construction operations (Bell 1951; Coopman et al. 2003; Ford et al. 1995; James 1963; Kleinfeld and Tabershaw 1954; McCarthy and Jones 1983; Pantucharoensri et al. 2004; Smith 1966; Thorburn et al. 2004). A number of the deaths occurred after the trichloroethylene exposure ended and involved physical exertion that may have contributed to the sudden deaths (Smith 1966; Troutman 1988). Deaths have also resulted from the early use of trichloroethylene as an anesthetic (DeFalque 1961) as well as the presumed intentional inhalation of concentrated fumes from trichloroethylene-containing substances (Clearfield 1970; Jones and Singer 2008; Takaki et al. 2008; Troutman 1988). Death associated with liver damage has also been reported in persons occupationally exposed to trichloroethylene for intermediate and chronic durations, followed by a high acute-duration exposure (Joron et al. 1955; Priest and Horn 1965). None of these cases provided adequate exposure level or duration data to define with accuracy the levels of inhalation exposure that cause human deaths. TRICHLOROETHYLENE 25 3. HEALTH EFFECTS In a cohort mortality study of 14,457 aircraft maintenance workers employed for at least 1 year between 1952 and 1956, a significant excess of death from asthma was found among 6,153 workers with reported occupational exposure to trichloroethylene; however, the workers were likely exposed to other chemicals as well (Blair et al. 1998). Animal experimentation has revealed inhaled concentrations that result in death following acute, intermediate, and chronic exposures. An LC50 value for acute exposure in rats was reported as 12,500 ppm for a 4-hour exposure (Siegel et al. 1971). Two out of 10 mice died after a 4-hour exposure to 6,400 ppm trichloroethylene (Kylin et al. 1962). Death was often caused by the central nervous system depression that occurs with very high exposure levels. Data on the lethality of longer-term exposure to trichloroethylene have been provided by studies of intermediate and chronic duration. Laboratory animals (rats, guinea pigs, monkeys, rabbits, and dogs) survived intermittent exposure to 700 ppm for 6 weeks or continuous exposure to 35 ppm for 90 days (Prendergast et al. 1967). There was no decrease in survival for rats and hamsters exposed to 500 ppm for 18 months, although a significant decrease in survival was seen for mice exposed to 100 ppm for the same amount of time (Henschler et al. 1980). All reliable LOAEL and LC50 values for death in each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 3.2.1.2 Systemic Effects The highest NOAEL values and all LOAEL values from each reliable study for each species, duration, and end point for systemic effects are recorded in Table 3-1 and plotted in Figure 3-1. Respiratory Effects. A worker developed labored breathing and respiratory edema after welding stainless steel that had been washed in trichloroethylene (Sjogren et al. 1991). The effects were attributed to inhalation of the trichloroethylene decomposition products, phosgene and dichloroacetyl chloride, although a history of cigarette smoking may have predisposed the subject to these respiratory effects. In a cohort mortality study of 14,457 aircraft maintenance workers employed for at least 1 year between 1952 and 1956, a significant excess of death from asthma (standardized mortality ratio [SMR] 160; 95% confidence interval [CI] 102–251) was reported for a group of 6,153 workers with reported occupational exposure to trichloroethylene compared to a referent group of workers not exposed to any chemical (Blair et al. 1998). The follow-up period was 1952–1990 and the trichloroethylene-exposed workers were likely exposed to other chemicals as well. Asthma-related symptoms and lung function decrements were TRICHLOROETHYLENE 26 3. HEALTH EFFECTS Table 3-1 Levels of Significant Exposure to Trichloroethylene - Inhalation Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments ACUTE EXPOSURE Death 1 Rat 4 hr 12500 M (LC50) Siegel et al. 1971 (Sprague- 12500 Dawley) 0009 2 Mouse 4 hr 6400 (2/10 deaths) Kylin et al. 1962 (Albino) 6400 0008 Systemic 3 Human 4 hr Hemato 95 M Konietzko and Reill 1980 95 0170 Hepatic 95 M 95 4 Human 5 d Hemato 200 Stewart et al. 1970 7 hr/d 200 0133 Hepatic 200 200 Ocular 200 (eye irritation) 200 5 Human 2.5 hr Cardio 200 M Windemuller and Ettema 1978 200 0156 6 Rat 6 hr Renal 1000 M (increased urinary Chakrabarti and Tuchweber (Fischer- 344) gamma-glutamyl 1988 transpeptidase, glucose, protein, serum urea nitrogen, decreased uptake of p-aminohippurate by renal cortical slices) 1000 0135 TRICHLOROETHYLENE 27 3. HEALTH EFFECTS Table 3-1 Levels of Significant Exposure to Trichloroethylene - Inhalation (continued) Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 7 Rat 1 or 2 wk Resp 376 M (nasal irritation during Kumar et al. 2002a (Wistar) 5 d/wk 4 h/d exposure) 376 9071 Ocular 376 M (ocular irritation during exposure) 376 8 Rat 6 hr Resp 500 F (reduction of aldrin Odum et al. 1992 (Alpk: APfSD) epoxidase and cytochrome C reductase activity) 500 1063 9 Rat 2 wk Bd Wt 1000 M Xu et al. 2004 (CD-1) 5 d/wk 1000 6 hr/d 9046 10 Mouse 6 hr Resp 20 F 100 F (vacuolization of Clara Odum et al. 1992 (CD-1) 20 cells, reduction of P-450 activity) 100 1061 11 Mouse 2 wk Resp 450 F (vacuolization of Clara Odum et al. 1992 (CD-1) 5 d/wk 6 hr/d cells, reduction of P-450 activity) 450 1062 TRICHLOROETHYLENE 28 3. HEALTH EFFECTS Table 3-1 Levels of Significant Exposure to Trichloroethylene - Inhalation (continued) Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 12 Mouse 7 d Ramdhan et al.