PHENOL 21 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 phenol. 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. It should be noted that phenol is the simplest form, or parent compound, of the class of chemicals commonly referred to as phenols or phenolics, many of which are natural substances widely distributed throughout the environment. There is some confusion in the literature as to the use of the term ‘phenol’; in some cases, it has been used to refer to a particular phenolic compound that is more highly substituted than the parent compound (Doan et al. 1979), whereas in other cases, it has been used to refer to the class of phenolic compounds (Beveridge 1997). This chapter, however, addresses only those health effects that can be directly attributable to the parent compound, monohydroxybenzene, or phenol. As Deichmann and Keplinger (1981) note: “It cannot be overemphasized that the structure-activity relationships of phenol and phenol derivatives vary widely, and that to accept the properties of individual phenolic compounds as being those of phenol is a misconception and leads to error and confusion.” A glossary and list of acronyms, abbreviations, and symbols can be found in Appendix C 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 PHENOL 22 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 A cohort mortality study of workers in five formaldehyde-resin manufacturing facilities was conducted to evaluate whether excess mortality could be attributed to occupational exposure to phenol (Dosemeci et al. 1991). Workers (exposed and non-exposed) had a mortality rate, from all causes, similar to that of the general U.S. population. Compared to either the general population or unexposed workers, exposed workers had small statistically non-significant excesses in mortality due to Hodgkin’s disease (standardized mortality ratio [SMR], 1.7; 95% confidence interval [CI], 0.8–3.1) and esophageal (SMR, 1.6; 95% CI, 0.9–2.6), renal (SMR, 1.3; 95% CI, 0.7–2.1), and rectal (SMR, 1.4; 95% CI, 0.8–2.2) PHENOL 23 3. HEALTH EFFECTS cancers. They also had small reductions in mortality due to: cancer of the stomach, testes, pancreas, buccal cavity/pharynx and brain; lymphosarcoma; liver cirrhosis; emphysema; diseases of the cardiovascular, circulatory, and digestive systems; motor vehicle accidents; and all accidents. The ambiguity of these data, as well as the fact that dose-related trends occurred only for those diseases showing reductions in mortality, makes it difficult to assess the impact on mortality of long-term occupational exposure to phenol. Deichmann et al. (1944) exposed guinea pigs, rabbits, and rats to phenol vapor at levels ranging from 26 to 52 ppm for 28–88 days. After 28 days of exposure, 5 of 12 guinea pigs died, but no deaths occurred in rabbits or rats. Since only a range was given for the exposure level, the exact level of phenol in air that resulted in death of guinea pigs was not established and may be as low as 26 ppm or as high as 52 ppm. Interpretation of this study is further complicated by an apparent lack of controls. However, since the effects observed in guinea pigs and rabbits (described in subsequent sections in Chapter 3) were so severe, it is difficult to ascribe the mortality to any source other than the phenol exposure. The lower limit of the exposure range, 26 ppm, is recorded as a serious LOAEL in Table 3-1 and plotted in Figure 3-1. No deaths were reported in Rhesus monkeys, rats, or mice exposed to 5 ppm phenol continuously for 90 days (U.S. Air Force 1961). 3.2.1.2 Systemic Effects The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. Respiratory Effects. Slight increases in mortality associated with respiratory cancers were seen in two epidemiological studies of workers exposed to phenol (Dosemeci et al. 1991; Kauppinen et al. 1986). However, after adjusting for smoking-related behavior, these increases became nonsignificant in the Kauppinen et al. (1986) study, and neither study showed a dose-related trend; thus, the relevance of these findings to respiratory disease per se is somewhat uncertain. Indeed in the latter study, there were slight, yet nonsignificant reductions in mortality associated with emphysema among exposed workers, leading the investigators to suggest that exposure to phenol could have a protective effect for diseases involving free radical damage. A case-control study of office workers was conducted by Baj et al. (1994) to evaluate the risks of chronic exposures to “inhaled formaldehyde, phenol, and isomers of organic chlorohydrocarbons from Ksylamit™ ...” which is a widely used liquid wood preservative. It should be noted that in the report, Table 3-1 Levels of Significant Exposure to Phenol - Inhalation PHENOL 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 Systemic 1 Rat 2 wk Resp 25 Hoffman et al. 2001 NOAELs are for organ (Fischer- 344) 5 d/wk 25 weights and 6 hr/d histopathology. 252 Hemato 25 25 Hepatic 25 25 Renal 25 25 Bd Wt 25 25 3. HEALTHEFFECTS 2 Mouse 5 min Resp 166 M (50% decrease in De Ceaurriz et al. 1981 (Swiss OF1) respiration rate) 166 086 Immuno/ Lymphoret 3 Rat 2 wk 25 Hoffman et al. 2001 NOAEL is for (Fischer- 344) 5 d/wk 25 histopathology of the 6 hr/d spleen. 253 4 Mouse 5 d 5 F Aranyi et al. 1986 NOAEL is for no (CD-1) 3 hr/d 5 change in susceptibility to infectious agents. 098 Neurological 5 Rat 1 hr 234 F Flickinger 1976 NOAEL is for no Harlan- 234 adverse neurological Wistar signs. 1 24 Table 3-1 Levels of Significant Exposure to Phenol - Inhalation (continued) PHENOL Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 6 Rat 8 hr 234 F (loss of coordination and Flickinger 1976 (Harlan- tremors) Wistar) 234 2 INTERMEDIATE EXPOSURE Death 7 Gn Pig 6 wk 26 (5/12 deaths) Deichmann et al. 1944 (NS) 5 d/wk 26 7 hr/d 065 Systemic 8 Monkey 90 d 3. HEALTHEFFECTS Resp 5 M U.S. Air Force 1961 NOAELs are for organ (Rhesus) 24 hr/d 5 histopathology. 106 Hemato 5 M 5 Hepatic 5 M 5 Renal 5 M 5 Bd Wt 5 M 5 9 Rat 15 d Hemato 26 Dalin and Kristoffersson 1974 (White) 24 hr/d 26 145 Hepatic 26 (serum activities of ALT, AST, LDH, and GLDH increased 2-6-fold; increased serum magnesium) 26 Bd Wt 26 26 25 Table 3-1 Levels of Significant Exposure to Phenol - Inhalation (continued) PHENOL Exposure/ LOAEL Duration/ a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments 10 Rat 10 wk Resp 26 Deichmann et al.