2.1. BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PHENOL IN THE UNITED STATES

Phenol is a naturally occurring and manufactured chemical that is widely distributed in the environment. It is found in various consumer products including throat lozenges, mouthwashes, and antiseptic lotions. The most likely route of exposure to phenol is through dermal contact either in the work environment or at home using ointments and other household products containing phenol.

Phenol is a product of combustion of coal wood and municipal solid waste; therefore, residents near coal and petroleum fueled facilities as well as residents near municipal waste incinerators may have increased exposure to phenol. Phenol is also a product of auto exhaust, and therefore, areas of high traffic likely contain increased levels of phenol. Recent data on concentrations of phenol in air are lacking; it was found at a median concentration of 30 parts per trillion (ppt) in 7 samples from one U.S. urban/suburban site in 1974 and at a median concentration of 5,000 ppt in 83 samples from seven sites between 1974 and 1978. The individual medians of the seven source sites ranged from 520 to 44,000 ppt. Higher phenol concentrations may occur when there is smog or in highly contaminated air.

Phenol has been detected in surface waters, rainwater, sediments, drinking water, groundwater, industrial effluents, urban runoff, and at hazardous waste sites. Levels of up to 1 ppb have been detected in unpolluted groundwater and concentrations ranging from 0.01 to 1 ppb were detected in unpolluted rivers. Phenol has been detected in Lake Huron water at 3–24 ppb and industrial rivers in the United States at 0–5 ppb.

Phenol generally does not adhere very strongly to soils and tends to filter rapidly through soil, which may account for the lack of monitoring data, since any phenol released to soils is likely to move to groundwater. In addition, phenol is readily biodegraded under both aerobic and anaerobic conditions, which is expected to attenuate its levels in soil.

Phenol is degraded rapidly in air (half-life of approximately 15 hours), but may persist in water for a somewhat longer period. In soil, phenol will biodegrade rapidly; the half-life in soil is generally <5 days.

Although low levels of phenol have been detected in certain foods and tap water, these levels do not constitute major sources of exposure for most people. Phenol has been reported at concentrations of 7 and 28.6 ppm in smoked summer sausage and smoked pork belly, respectively, and was identified but not quantified in mountain cheese, fried bacon, fried chicken, and black fermented tea.

Since plants can metabolize phenol readily, exposure through eating food derived from plants grown in phenol-containing soil is probably minimal. Due to rapid biodegradation in water and soil, this contamination should be limited. People with contaminated tap water can be exposed from drinking the water or eating foods prepared with it. In addition, inhalation can occur during showering, bathing, and cooking with contaminated water. People can also be exposed to phenol through dermal contact due to bathing or showering with contaminated water.

There are no known unique sources of exposure to children. No reports of phenol in breast milk or baby foods were found. Children are likely to be exposed to phenol through inhalation of contaminated air from wood, coal, and waste incineration as well as from second-hand smoke. Nonsmokers who live with smokers may be exposed to 6–14 μg/day of phenol.

2.2. SUMMARY OF HEALTH EFFECTS

Information about the health effects of phenol in humans is derived from studies of workers and members of the general population following inhalation, oral, and dermal exposure. These studies indicate that phenol is an irritating and corrosive substance, making the skin and mucosal membranes targets of toxicity, but other effects have also been reported. However, the data for humans exposed to phenol by inhalation or ingestion are inadequate to establish concentration-response relationships, which are needed to identify adverse effects levels. Fatalities due to ingestion or contact with a significant area of the skin have been reported. A minimal lethal oral dose of approximately 70 mg/kg has been estimated in adults. Other estimates indicate that an oral dose as low as 1,000 mg could be fatal in humans, but patients occasionally survived doses as high as 65,000 mg. Postmortem examination typically showed serious mucosal alterations in the gastrointestinal tract. Other than the skin and mucosal membranes, the liver and cardiovascular system might by considered targets for phenol toxicity. In an epidemiological study of workers from the rubber industry exposed to multiple chemicals (phenol among them), phenol showed the strongest association with mortality due to ischemic heart disease. Electrocardiographic alterations have been reported following acute oral and dermal exposure to phenol, as well as vomiting and lethargy. Studies of populations whose drinking water was contaminated with phenol found increased incidences of nausea and diarrhea, but exposure to chlorophenols may have also occurred. Also, liver effects, as judged by increased serum activities of alanine aminotransferase (ALT) and aspartate amino transferase (AST), were reported in a case of prolonged inhalation exposure to phenol and in workers in an oil-refining plant, but exposure to other solvents could not be ruled out in the latter case. An increased incidence of headaches was reported among people who used drinking water contaminated with phenol and probably chlorophenols also. There is no evidence that phenol is a reproductive or developmental toxicant in humans. The Development and Reproductive Toxicant Identification Committee of the California EPA’s Office of Environmental Health Hazard Assessment examined the weight of evidence on the reproductive toxicity of phenol and concluded that phenol had not been clearly shown to cause reproductive toxicity.

There is only one modern study of inhalation exposure of animals to phenol. The rest of the inhalation database for phenol is outdated and not useful for risk assessment, although it serves to identify some targets for phenol toxicity. However, no single especially sensitive target emerged from these studies. Short-term (5 minutes) exposure of mice to phenol caused respiratory irritation, as judged by the animals’ reflex reduction in respiratory rate; a lowest-observed-effect level (LOEL) was not defined; but the exposure concentration that reduced the respiratory rate by 50% was 166 ppm. In rats exposed nose-only intermittently to concentrations up to 25 ppm for 2 weeks, phenol caused no gross or microscopic alterations in major tissues and organs, including the nasal cavity, but some rats showed an increased incidence in a red nasal discharge possibly due to the irritating properties of phenol. Phenol caused pneumonia, necrosis of the myocardium, centrilobular degeneration, and necrosis of the liver and renal lesions in rabbits and guinea pigs, but not in rats, exposed whole-body intermittently to 26 ppm phenol for intermediate durations. In yet another study in rats, continuous whole-body exposure to 26 ppm phenol for 15 days caused signs of neurological impairment including muscle tremors, twitching, and gait disturbances during the first 3–5 days of exposure. At termination, serum transaminases were elevated suggesting liver damage, but no histological examination was conducted. Neurological effects, including loss of coordination and tremors, were also observed in rats exposed to 234 ppm phenol for 8 hours. In summary, inhaled phenol can affect several organs and tissues and produce neurological effects, but few generalizations can be made from the available studies due to the different exposure protocols used (i.e., nose-only vs. whole-body; intermittent vs. continuous) and incomplete reporting. Toxicokinetics information indicates that phenol is readily absorbed through the skin of humans and animals, so that whole-body exposure may result in considerably more absorbed phenol than in nose-only exposures.

Application of phenol to the skin of animals has caused edema, erythema, necrosis, and death; the cause of death was not provided in the studies available. The effects of phenol on the skin are due to its property to impair the stratum corneum and produce coagulation necrosis by denaturing and precipitating proteins. Lethality is influenced by the surface area exposed as well as the concentration of the applied solution. Systemic effects also have been described in animals following dermal exposure to phenol. Rabbits that received a dose of phenol of 24 mg/cm²/kg suffered cardiac arrhythmia. Tremors leading to convulsions were reported in rats following application of 107 mg/kg of phenol to an unspecified surface area.

In contrast to the limited inhalation database, there is an extensive database of oral studies in animals; yet, it is not easy to characterize the toxicity of orally administered phenol. A key factor contributing to the inability to do so is that phenol administered by oral gavage is much more toxic than when it is administered in the drinking water, a phenomenon that is related to the toxicokinetics of phenol. Studies have shown that the toxicity of phenol is correlated with peak blood concentration rather than with total dose, such as the area under the blood concentration curve (AUC). Thus, end points that appear sensitive to phenol administered by oral gavage are not affected by the same total daily dose given via the drinking water.

Results from a 28-day drinking water study in mice provided the lowest effect levels in the oral database for phenol and suggested that hematological, neurochemical, and immunological end points may be particularly sensitive to phenol toxicity. However, since the effects reported in that study occurred at dose levels much lower than in any other study available, these findings should be interpreted with caution until supporting results are available. In one study, phenol induced a significant decrease in red blood cell counts in mice at ≥1.8 mg/kg/day. While this finding could have been due to macrocytosis, the study did not provide enough information to evaluate this possibility. Only two additional studies provided information on hematological parameters after phenol exposure. In pregnant mice, a single gavage dose of 265 mg/kg of phenol (only dose tested) on gestation day (GD) 13 induced a reduction in the ratio of poly/normochromatic erythrocytes in the bone marrow, whereas phenol administered to rats in doses of up to 320 mg/kg/day in the drinking water for 10 weeks did not significantly affect a comprehensive number of hematological parameters monitored. Other long-term drinking water studies in rats and mice did not evaluate hematological parameters.

The neurochemical effects caused by phenol in a study also occurred at ≥1.8 mg/kg/day and consisted of alterations in the levels of neurotransmitters in various brain areas. This is difficult to interpret in light of the absence of clinical signs and lack of supporting evidence from other studies. Phenol, however, did induce neurological effects in other studies. Short-term oral gavage administration of doses ≥120 mg/kg/day of phenol caused muscle twitching and tremors in rats and mice, but no effects were observed at <40 mg/kg/day. Decreased motor activity was reported in female rats dosed with 360 mg/kg/day of phenol in the drinking water for 13 weeks, but no effects were seen at 107 mg/kg/day. No neurochemical evaluations were conducted in these studies. Other long-term drinking water studies in rats and mice that used much higher doses of phenol did not observe significant changes in gross or microscopic appearance of the brain of the animals, but no neurological tests or neurochemical evaluations were conducted in these studies.

Phenol caused a significant decrease in antibody response to immunization with sheep red blood cells (SRBC) in mice at ≥6.2 mg/kg/day in a drinking water study. Lymphoproliferative responses to T and B cell mitogens were also significantly suppressed at 33.6 mg/kg/day. A study in which the plaque-forming cell assay to SRBC (but not the antibody titer) and lymphoreticular organs of rats exposed to up to 321 mg/kg/day of phenol in the drinking water for 10 weeks were evaluated found no significant alterations. In another study, a single dose of 224 mg/kg of phenol administered to rats by oral gavage caused necrosis or atrophy of the spleen or thymus, but no other immunological end point was evaluated. Long-term drinking water studies in rats and mice did not report any significant gross and histological alteration in lymphoreticular organs and tissues at phenol doses >1,000 mg/kg/day.

Other effects of phenol observed in oral studies include renal tubular necrosis in rats treated with a single gavage dose of 224 mg/kg or with 40 mg/kg/day for 14 days. However, long-term drinking water studies in rats and mice that received much higher doses of phenol do not suggest that the kidney is a particularly sensitive target for phenol. Phenol also induced decreases in body weight in rats and mice in 13-week and 2-year drinking water studies that were associated with significant reductions in water consumption due probably to poor palability. Phenol reduced body weight gain in pregnant mice treated by oral gavage with 280 mg/kg/day, a dose level that also caused frank neurotoxicity. Doses of 120 mg/kg/day of phenol administered to pregnant rats during GDs 6–15 using a divided dosing protocol to minimize the adverse effects of a bolus dose caused a significant reduction in weight gain in the dams; the no-observed-adverse-effect level (NOAEL) was 60 mg/kg/day. The latter findings suggest that weight gain during pregnancy is a sensitive end point for phenol toxicity and the dose of 120 mg/kg/day was the lowest LOAEL in acute-duration oral studies in which no overt signs of toxicity (other than reduced maternal weight gain) were observed following administration of phenol.

Phenol has induced developmental effects in rodents, but, with one exception, it appears that this occurs at dose levels that also affect the mothers. In one study, doses of 120 mg/kg/day of phenol on GDs 6–15 produced a 7% decrease in average fetal body weight in the absence of maternal effects. In the study that used the divided dosing protocol mentioned above, there were no developmental effects at 120 mg/kg/day, but decreased ossification sites were seen at the highest dose level, 360 mg/kg/day. In a two-generation reproductive study in which the parental generation received doses of up to 301–321 g/kg/day of phenol via the drinking water, decreased pup weight and percent live pups on postnatal day 4 was reported at a dose level that also significantly decreased maternal water consumption, including during gestation and lactation. In pregnant mice, doses of 280 g/kg/day on GDs 6–15 produced a significant decrease in fetal weight and also caused tremors and ataxia in the dams.

A study of phenol-exposed wood industry workers reported a small, nonsignificant excess of respiratory cancers and a study of phenol production workers reported a small, non-significant excess of Hodgkin’s disease and of lung, esophageal, rectal, and kidney cancers. However, the interpretation of these findings is complicated due to lack of dose-response and potential for confounding. Phenol has been tested for carcinogenicity in long-term drinking water bioassays in rats and mice. Statistically significant increased incidences of pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in male rats exposed to the low dose of phenol, but not to the high dose of phenol. No significant effects were seen in female rats or in mice. Phenol has consistently been found to be a promoter in initiation-promotion studies in mouse skin. Based on inadequate evidence in humans and in animals, EPA assigned phenol to Group D, not classifiable as to human carcinogenicity. Under updated guidelines, the data regarding carcinogenicity of phenol are: “inadequate for an assessment of human carcinogenic potential.”

2.3. MINIMAL RISK LEVELS (MRLs)

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for phenol. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised.