CRESOLS
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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 168
CRESOLS
This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.
First draft prepared by Dr L. Papa, US Environmental Protection Agency, Cincinnati, USA
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the World Health Organization
World Health Organization Geneva, 1995
The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main
objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of
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development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and
epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals.
WHO Library Cataloguing in Publication Data Cresols
(Environmental health criteria ; 168) 1.Cresols - adverse effects
2. Environmental exposure I.Series
ISBN 92 4 157168 1 (NLM Classification: QV 223) ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS 1. SUMMARY
1.1. Identity, properties and analytical methods 1.2. Uses, sources and levels of exposure
1.3. Kinetics and metabolism
1.4. Effects on laboratory mammals; in vitro systems 1.5. Effects on humans
1.6. Effects on other organisms 1.7. Conclusion and recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1. Identity
2.2. Physical and chemical properties 2.3. Conversion factorsl
2.4. Analytical methods 2.4.1. Sampling
2.4.2. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence 3.2. Anthropogenic sources
3.2.1. Production levels and processes 3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1. Transport and distribution between media
4.1.1. Air 4.1.2. Water 4.1.3. Soil 4.2. Transformation
4.2.1. Abiotic transformation 4.2.2. Biodegradation
4.3. Bioaccumulation and biomagnification 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels 5.1.1. Air
5.1.2. Water 5.1.3. Soil
5.1.4. Food and beverages 5.2. General population exposure 5.3. Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation 6.4. Elimination and excretion 6.5. Endogenous cresols
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1. Single exposure
7.1.1. Inhalation route 7.1.2. Oral route
7.1.3. Dermal route 7.2. Short-term exposure
7.2.1. Inhalation route 7.2.2. Oral route
7.3. Long-term exposure
7.3.1. Inhalation route 7.3.2. Oral route
7.4. Skin and eye irritation
7.5. Reproductive toxicity, embryotoxicity and teratogenicity 7.5.1. Reproduction
7.5.2. Embryotoxicity and teratogenicity 7.6. Mutagenicity and related end-points
7.7. Carcinogenicity
7.8. Other special studies
7.8.1. Neurological effects 7.8.2. Effects on the skin
7.9. Mechanism of toxicity - mode of action 8. EFFECTS ON HUMANS
8.1. General population exposure 8.1.1. Poisoning incidents 8.1.2. Controlled human studies 8.1.3. Cancer
8.2. Occupational exposure
8.2.1. Poisoning incidents 8.2.2. Epidemiological studies 8.3. Subpopulations at special risk
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1. Microorganisms
9.1.1. Aquatic
9.1.1.1 Laboratory studies 9.1.1.2 Field studies
9.1.2. Terrestrial
9.1.2.1 Laboratory studies 9.1.2.2 Field studies
9.2. Plants
9.2.1. Aquatic
9.2.1.1 Laboratory studies 9.2.1.2 Field studies
9.2.2. Terrestrial
9.2.2.1 Laboratory studies 9.2.2.2 Field studies
9.3. Invertebrates 9.3.1. Aquatic
9.3.1.1 Laboratory studies 9.3.1.2 Field investigations
9.3.2. Terrestrial
9.3.2.1 Laboratory studies 9.3.2.2 Field studies
9.4. Vertebrates 9.4.1. Aquatic
9.4.1.1 Laboratory studies 9.4.1.2 Field studies
9.4.2. Terrestrial
9.4.2.1 Laboratory studies 9.4.2.2 Field studies
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of human health risks
10.2. Evaluation of environmental risks 10.3. Guidance value
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH 11.1. Conclusions
11.2. Recommendations 12. FURTHER RESEARCH
REFERENCES RESUME RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are kindly requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda.
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A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).
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This publication was made possible by grant number
5 U01 ES02617-15 from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, and by financial support from the European Commission.
Environmental Health Criteria PREAMBLE
Objectives
In 1973 the WHO Environmental Health Criteria Programme was initiated with the following objectives:
(i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits;
(ii) to identify new or potential pollutants;
(iii) to identify gaps in knowledge concerning the health effects of pollutants;
(iv) to promote the harmonization of toxicological and
epidemiological methods in order to have internationally comparable results.
The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976 and since that time an everincreasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth.
Since its inauguration the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals.
The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently the work became an integral part of the International Programme on Chemical Safety (IPCS), a
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Content
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* Summary - a review of the salient facts and the risk evaluation of the chemical
* Identity - physical and chemical properties, analytical methods * Sources of exposure
* Environmental transport, distribution and transformation * Environmental levels and human exposure
* Kinetics and metabolism in laboratory animals and humans * Effects on laboratory mammals and in vitro test systems * Effects on humans
* Effects on other organisms in the laboratory and field
* Evaluation of human health risks and effects on the environment * Conclusions and recommendations for protection of human health and the environment
* Further research
* Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR
Selection of chemicals
Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment;
the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for environment; international concern, i.e.
the substance is of major interest to several countries; adequate data on the hazards are available.
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WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS Members
Dr D. Anderson, British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom
Dr M.R. Elwell, National Institute of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
Dr A. Meharg, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, United Kingdom
Dr C.-N. Ong, Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore
(Vice-Chairman)
Dr Y. Pang, Division of Standard Setting, Chinese Academy of Preventive Medicine, Beijing, China
Dr L. Papa, System Toxicants Assessment Branch, Office of Research and Development, Environmental Criteria and Assessment Office, US
Environmental Protection Agency, Cincinnati, Ohio, USA (Rapporteur)
Dr A. Pinter, National Institute of Hygiene, Budapest, Hungary Dr S. Soliman, Pesticide Chemistry and Toxicology, College of Agriculture and Veterinary Medicine, Bureidah, Saudi Arabia
Dr F.M. Sullivan, Division of Pharmacology and Toxicology, St Thomas's Hospital, London, United Kingdom (Chairman)
Secretariat
Dr B.H. Chen, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary)
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, Lyon, France
ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS
A WHO Task Group on Environmental Health Criteria for Cresols met at the British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom, from 27 June to 1 July 1994. Dr D. Anderson opened the meeting and welcomed the participants on behalf of the host institution. Dr B.H. Chen, IPCS, welcomed the participants on behalf of the Director, IPCS, and the three cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and revised the draft monograph and made an evaluation of the risks for human health and the environment from exposure to cresols.
Drs N.N. Molodkina, L.P. Kuzmina and A.L. Germanova, Centre for International Projects, Moscow, Russian Federation, prepared a
preliminary draft. The first draft of this monograph was prepared by Dr L. Papa, US Environmental Protection Agency, Cincinnati, USA. The second draft was also prepared by Dr L. Papa, incorporating comments received following the circulation of the first draft to the IPCS Contact Points for Environmental Health Criteria monographs.
Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content and technical editing, respectively.
The efforts of all who helped in the preparation and finalization of the monograph are gratefully acknowledged.
* * * *
Financial support for this Task Group was provided by the United Kingdom Department of Health as part of its contributions to the IPCS.
1. SUMMARY
1.1 Identity, properties and analytical methods
Cresols are isomeric substituted phenols with a methyl
substituent at either the ortho, meta or para position relative to the hydroxyl group. Commercial cresol, also known as cresylic acid, contains all three isomers with small amounts of phenol and xylenols.
However, commercial products contain up to 30% xylenol and 60%
C9-phenols and are known as "cresylic acids". Physically, cresols consist either of a white crystalline solid or a yellowish liquid and have a strong, phenol-like odour. They are highly flammable and are soluble in water, ethanol, ether, acetone and alkali hydroxides.
Cresols undergo electrophilic substitution reactions at the vacant ortho or para position relative to the hydroxyl group. They also undergo condensation reactions with aldehydes, ketones or dienes.
Several methods can be used for determining the presence of
cresols in both environmental and biological media. The most commonly used methods are gas chromatography with flame ionization detection (GC-FID), gas chromatography with mass spectrophotometry (GC-MS) and high-performance liquid chromatography (HPLC). Sampling of cresols in air can be done by passing air through absorption cells using sodium hydroxide or solid adsorbents.
1.2 Uses, sources and levels of exposure
Cresols have a wide variety of uses as solvents or disinfectants or as intermediates in the production of numerous other substances.
These compounds are most commonly used in the production of
fragrances, antioxidants, dyes, pesticides and resins. Ortho- and para-cresols are used in the production of lubricating oils, motor
fuels and rubber polymers, while meta-cresol is used in the manufacture of explosives.
Cresols and cresol derivatives occur naturally in oils of various plants, including Yucca gloriosa flowers, jasmine, Easter lily,
conifers, oaks and sandalwood trees, and are also a product of
combustion from natural fires and volcanic activity. Para-cresol is found in the urine of animals and humans. Commercially cresols are produced as by-products in the fractional distillation of crude oil and coal tars. Small amounts are produced in vehicle exhaust, municipal waste incinerators and from coal and wood combustion.
Cigarette smoke also contains cresols. The worldwide production of cresols is unknown; annual production in the USA in 1990 was reported to be 38 300 tonnes.
Environmental transport of cresols occurs through the vapour phase of the atmosphere and from the atmosphere to surface water and soil by rain-scavenging. Due to their volatilization, binding to sediment and biodegradation, only small amounts of cresols are found in water. In soils, cresols are slightly to highly mobile depending on the sorption coefficient (Koc) of the soil. Cresols have been
detected in ground water, and so leaching must occur in soil.
Exposure to cresols can occur through air, water or food. The median air concentration of o-cresols was 1.59 µg/m3 (0.359 ppb) for 32 source-dominated sites in the USA. Surface water
concentrations in the USA range from below the detection limit to 77 µg/litre (STORET, 1993). Levels of 204 µg/litre were reported in Japan in a river polluted by industrial effluents. Concentrations as high as 2100 µg/litre for o-cresol and 1200 µg/litre for mixed
m- and p-cresols have been detected in waste waters. Rainwater concentrations range from 240 to 2800 ng/litre for o-cresol and 380 to 2000 ng/litre for p- and m-cresol combined. Cresols have been detected in foods and beverages. Concentrations in spirit bever!ges were found to be within the range of 0.01-0.2 mg/litre. The amount in tobacco smoke is 75 µg in a nonfilter American cigarette (85 mm). The general population can be exposed to cresols from air inhalation, drinking-water, food and beverage ingestion and dermal contact. In general, the lack of adequate monitoring data makes the quantitative estimates of daily intakes of cresol from these sources impossible.
Occupational exposure levels as high as 5.0 mg/m3 have been reported.
1.3 Kinetics and metabolism
Cresols are absorbed across the respiratory and gastrointestinal tracts and through the skin. The rate and extent of absorption of cresols has not been studied specifically. However, studies have shown that gastrointestinal and dermal absorption are rapid and extensive. Cresols are distributed to all the major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor metabolic pathways for cresols include hydroxylation of the benzene ring and side-chain oxidation.
The main route for elimination of cresols from the body is renal excretion in the form of conjugates.
1.4 Effects on laboratory mammals; in vitro systems
Acute poisoning with cresol vapours is unlikely due to the low vapour pressure of these compounds. Mean lethal concentrations of cresols in rats have been reported to be 29 mg/m3 for o- and
p-cresols and 58 mg/m3 for m-cresol. Oral LD50 values in rats have been reported to be 121, 207 and 242 mg/kg body weight for o-,
p- and m-cresols, respectively. Interspecies comparisons show
that all three isomers are more toxic to mice than to rats and that toxicity increases with concentration. Systemic toxicity and death can result from dermal exposure. Dermal LD50 values in rabbits were 890, 2830, 300 and 2000 mg/kg body weight for o-, m-, p-and mixed cresols, respectively. In rats dermal LD50 values were 620, 1100, 750 and 825 mg/kg body weight for o-, m-, p- and dicresol, respectively.
Cresols are highly irritating to the skin and eyes of rabbits, rats and mice.
Short-term exposure to inhaled mixtures of o-cresol aerosol and vapour resulted in irritation of the respiratory tract, small
haemorrhages in the lung, body weight reduction and degeneration of heart muscle, liver, kidney and nerve cells. Short-term (28-days) oral exposure to daily doses of approximately 800 mg/kg body weight or more resulted in reduced body weights, organ weight changes and
histopathological changes in the respiratory and gastrointestinal tracts of rats. In mice, similarly exposed at 1500 mg/kg body weight, more severe effects were reported, and at the highest concentrations death resulted from exposure to o-, m- and p-cresols but not from exposures to mixtures of isomers.
Longer-term exposure of rats to vapours of o-, m- or p-cresol for up to 4 months resulted in weight loss, reduced locomotor activity, inflammation of nasal membranes and skin, and changes in the liver. Oral exposures for up to 13 weeks of mice, rats and hamsters resulted in mortality, tremor, reduced body weights, haematological effects, increase in organ weight, and hyperplasia of nasal and forestomach epithelium.
Oral and inhalation exposure to cresol isomers result in
lengthened estrus cycle and histopathological changes in the uterus and ovaries of rats and mice. No adverse effects on spermatogenesis were observed in rats or mice. Mild fetotoxic effects have been reported in rats and rabbits exposed to o- and p-cresols, but only minor treatment-related developmental effects have been reported.
Some evidence of genotoxicity has been reported to result in vitro from treatment with o- and p- cresols but not m-cresol. No positive results were obtained in in vivo studies. However, some evidence of promotive activities in skin has been reported. No
studies of carcinogenicity have been reported for any cresol isomers.
1.5 Effects on humans
Ingestion of cresols results in burning of the mouth and throat, abdominal pain and vomiting. The target tissues/organs of ingested cresols in humans are the blood and kidneys, and effects on the lungs, liver, heart and central nervous system have also been reported. In severe cases, coma and death may result. Dermal exposure has been reported to cause severe skin burns, scarring, systemic toxicity and death.
Occupational exposure to cresols usually results from dermal contact. Acute exposures can result in severe burns, anuria, coma and death. Very few data are available regarding reproductive effects and there are no data on carcinogenicity in humans.
1.6 Effects on other organisms
Observations on microorganisms, invertebrates and fish have shown that cresols may represent a risk to non-mammalian organisms at point sources with high cresol concentration but not in the general
environment.
1.7 Conclusion and recommendations
At concentrations normally found in the environment, cresols do not pose any significant risk for the general population. However, the potential for adverse health effects exists in the case of people with renal insufficiency or specific enzymic deficiency and under conditions of high exposure.
Cresols may represent a risk to microorganisms, invertebrates and fish at point sources with high cresol concentrations but not in the general environment.
No information is available regarding the effects of chronic exposure to cresols. Therefore, there is inadequate information to assess the carcinogenic hazard of cresols. Based on the results of subchronic studies, an NOAEL of 50 mg/kg body weight per day can be established for all three cresol isomers. An uncertainty factor of 300 was recommended, composed as follows: 10 to account for
interspecies variation; 10 to account for the lack of chronic toxicity studies and possible genotoxic and promoting activity of cresols, and 3 to account for intraspecies variation based on the rapid and
complete metabolism. Therefore, an acceptable daily intake (ADI) of 0.17 mg/kg body weight per day can be established for cresols.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1 Identity
Cresols are isomeric substituted phenols with a methyl
substituent at either the ortho, meta or para positions relative to the hydroxyl group. Commercial cresol, also known as cresylic acid, contains all three isomers with small amounts of phenol and xylenols (Deichmann & Keplinger, 1981). Mixtures of m- and p-cresol and of
o-, m- and p-cresol are occasionally called dicresol and
tricresol, respectively (Fiege & Bayer, 1987). Pure and commercial cresol or cresylic acid is different from the commercial products called "cresylic acids". The substance "cresylic acids" is a mixture of phenolic compounds with a typical composition as follows: 0-1% m- and p-cresol; 0-3% 2,4- and 2,6-xylenols; 10-20% 2,3- and
3,5-xylenols; 20-30% 3,4-xylenol; and 50-60% C9-phenols (Sax & Lewis, 1987). The chemical identity of cresols is shown in Table 1.
Commercial cresols are manufactured in a wide range of grades and purities to suit the user's requirements. Typically, technical grade cresol available in the USA contains about 20%
o-cresol, 40% m-cresol, 30% p-cresol, and 10% phenol and
xylenols (Deichmann & Keplinger, 1981). The individual isomers are available at purity levels as low as 85% and as high as > 99% from chemical suppliers in the USA.
2.2 Physical and chemical properties
The physical properties of the three individual isomers and the mixture are given in Table 2.
Chemically, cresols behave similarly to phenol. These compounds undergo electrophilic substitution reactions at the vacant ortho or
para position relative to the hydroxyl group. Chlorination, bromination, sulfonation and nitration are examples of such
substitution reactions. Cresols can undergo condensation reactions with aldehydes, ketones and dienes (Fiege & Bayer, 1987).
2.3 Conversion factors
Air at 25°C: 1 ppm = 4.42 mg/m3 1 mg/m3 = 0.23 ppm
Table 1. Chemical identity of cresols
o-Cresol p-Cresol
Chemical structure:
Empirical formula: C7H8O C7H8O C Relative molecular mass: 108.14 108.14 Common synonyms: 2-methyl phenol 4-methyl phenol 2-hydroxy toluene 4-hydroxy toluene o-cresylic acid p-cresylic acid
IUPAC name: 2-hydroxy toluene 4-hydroxy toluene CAS registry number: 95-48-7 106-44-5 RTECS: G06300000 G06475000 EEC number: 604-004-00-9 604-004-00-9
Table 2. Physical and chemical properties of cresolsa
o-Cresol m-Cresol
Physical state and colour: white crystalline solid colourless to or yellowish liquid liquid yellowi Odour: phenol-like phenol-like Air odour thresholdb: 1.4 mg/m3 0.007 mg/m3 Melting point (°C): 30.94 12.22 Boiling point at 1 atm (°C): 191.0 202.32 Flash point, closed cup (°C): 81 86 Ignition point (°C): 598 558 Vapour pressure at 25°C (mmHg): 0.31 0.143
Relative density at 25°C (g/cm3): 1.135 1.030 Refractive index at 25°C: 1.544 1.540 Vapour density (air = 1 at 20°C): 3.7 3.72 Solubility in water at 25°C
(g/litre)c: 25.95 22.70 Solubility in other solvents: soluble in ethanol, soluble in eth ethyl ether, acetone, ethyl ether, a benzene, aqueous benzene, aqueo alkali hydroxides alkali hydroxi
Table 2 (contd).
o-Cresol m-Cresol
Sorption coefficient,
Koc (all isomers)d 22-3420 Log n-octanol/water partition
coefficiente (log Ko/w): 1.95 1.96 pKa (25°C): 10.287 10.09 Bioconcentration factorsh 14.1 19.9 Odour threshold in water
(mg/litre)i,j 1.4 0.8 Taste threshold concentration
in water (mg/litre)j 0.003 0.002 Saturation concentration
in air (g/m3)j at 20°C 1.2 0.24 at 30°C 2.8 0.68
a Adapted from: Weast et al. (1988); Sax & Lewis (1987); Windholz et al. (
b Amoore & Hautala (1983)
c Yalkowsky et al. (1987)
d Boyd (1982); Southworth & Keller (1986); Koch & Nagel (1988)
e Hansch & Leo (1985)
f No data
g Parrish (1983)
h Freitag et al., (1982)
i Dietz & Traud (1978)
j Verschuesen (1983)
2.4 Analytical methods
2.4.1 Sampling
As is the case with any other analyte, sample loss and
contamination should be avoided during the collection, storage and analysis of samples for cresol determination. Glass bottles, vials or
tubes have been used for the collection of environmental samples (US EPA, 1982). Polyethylene containers are suitable for the collection of biological samples (US NIOSH, 1989). Environmental aqueous samples can be stored for a limited time (28 days) by adding sulfuric acid to a pH < 2 (US EPA, 1982). Thymol has been used as a preservative for biological samples (US NIOSH, 1989). Environmental and biological samples that are to be shipped from the collection site to the laboratory are cooled in ice.
Cresols in air can be sampled by passing air through an absorption cell containing 0.1 N sodium hydroxide solution (Manita, 1966). More recent methods use solid adsorbents such as XAD-2 or silica gel for trapping cresols from air (Neiminen & Heikkila, 1986;
US NIOSH, 1989). In a novel system, a miniaturized enrichment unit has been used to concentrate cresols and other water-soluble analytes in air by a water mist (Vecera & Janak, 1987). Aqueous samples can be collected either by manual grab methods or by automated samplers.
Composite samples can be obtained by combining random samples
collected manually or by automated samplers (US EPA, 1982). Several mechanical devices are available for collecting random or composite semi-solid and solid samples either by grab or automated methods (US EPA, 1982, 1986).
2.4.2 Analytical methods
Some of the methods used in measuring cresols in various environmental and biological media are given in Table 3 along with their corresponding references. The problem with the determination of cresols by gas chromatography arises as a result of non-reproducible elution from the gas chromatography column due to the polar and
volatile nature of cresols. Special columns or derivatization of the cresols may alleviate the problem. Cresols are present in biological samples as conjugates, and a hydrolysis method is used to release free cresols. There is no consensus on the reliability of total hydrolysis of the cresol conjugates (Balikova & Kohlicek, 1989).
Chudyk et al. (1985) tested a remote fluorescence technique using ultraviolet laser fibre optics to analyse groundwater contaminants, including o-cresol, in artificially prepared solutions. No data were given on the detection limits or on the use of this technique in the field. However, the authors speculated that the sensitivity is at or below parts per billion levels at an instrument/analyte distance of 25 m.
Hoshika & Muto (1978) described a simple and rapid
gas-liquid-solid chromatographic (GLSC) method for the determination of trace concentrations of 11 phenols including all isomers of cresol in air. This method has been adopted and recommended by many other investigators for measuring cresols in air samples. To overcome
interference by certain acidic compounds such as lower fatty acids and mercaptans, the method uses two precolumns, a Tenax-GC and a Tenax-GC plus alkaline. The gas chromatograph used was equipped with a flame ionization detector (FID), a digital integrator and a glass analytical column. With the Tenax-GC plus alkaline precolumn the phenol peaks disappeared completely in the chromatograms, enabling phenols to be identified by comparison with the chromatograms from the ordinary Tanex-GC precolumn. The detection limit for cresols by this method was reported to be at the ppb level.
Table 3. Sampling and analytical methods for determining cresols in envi
Sample Analytical
matrix Preparation method methodb
Air
Air pump air through adsorbent tube; HPLC/UV desorb with methanol Air aerodispersive enrichment into HPLC/ED water Air pump air through silica gel tube; GC-FID desorb with acetone 22 mg/m3
Air pump air through mixed cellulose HPLC-UV ester membrane connected to silica
Sep-Pak, desorp with 1% acetic acid in acetonitrile
Auto exhaust vapour collected in fritted bubbler HPLC-UV and tobacco with aqueous NaOH buffered to pH 11.5;
smoke add p-nitrobenzene-diazonium
tetra-fluoroborate; extract with CCl4 Air and water
Air and water mix NaOH solution from bubbler in case spectrophotometry of air and distillate of water samples (TLC) in 1 N NaOH solution with
p-nitrophenyl-diazonium at pH 7-9;
extract with ether; spot on TLC plate
Table 3 (contd).
Sample Analytical matrix Preparation method methodb
Water adjust pH to 11; extract with GC/MS CH2Cl2; concentrate
Water solvent extraction, liquid GC/MS chromatography prefractionation Water adjust pH to 8-9; extract with spectrophotometry chloroform-ether; back extract (VIS) in 0.1 N aqueous NaOH; add NaNO2
and H2SO4; remove excess NO;
add resorcinol
Water direct flow and spectrophotometry stopped-flow injection, then (VIS) derivatization with p-aminophenol
Rainwater direct injection onto ion exchange HPLC/CD column Rainwater acidify; extract with CH2Cl2; GC/MS concentrate, methylate Soil
Soil, extract sample with CH2Cl2 using GC/MS sediment ultrasonic probe
Table 3 (contd).
Sample Analytical matrix Preparation method methodb
Sediment extract rapidly stirred sediment GC/MS slurry with CH2Cl2 or ether, concentrate
Biological samples
Expired draw air through XAD-2 adsorbent HPLC/ED air tube; acetonitrile desorbtion Expired collect breath in Teflon bag; GC/MS air concentrate on Tenax GC absorbent;
thermal desorption
Beef steam distil; extract distillate HRGC/MS with ether
Urine hydrolyse with sulfuric acid; GC/FID extract with ethyl acetate Urine hydrolyse with HCl and extract with HPLC/UV isopropyl ether; remove solvent;
dissolve residue in water; add ß-cyclodextrin
Urine acidify; steam distil; extract with GC/MS methylene chloride Urine hydrolyse with sulfuric acid; extract HPLC/UV with CH2Cl2; concentrate
Table 3 (contd).
Sample Analytical matrix Preparation method methodb
Urine hydrolyse with HCl or HClO4; extract GC-FID with ether Urine and hydrolyse with H3PO4; extract with GC-FID serum n-hexane, acetylate extract
Faeces and homogenize faeces and hydrolyse HPLC-fluorescence urine urine buffered to pH 5.5, steam detector distil
a 0.01 nmol = 1.08 ng
b CD = conductivity detector; ED = electrochemical detector; FID = flame i HPLC = high-performance liquid chromatography; HRGC = high-resolution ga o = ortho-cresol; p = para-cresol; UV = ultraviolet detector
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence
Cresols and cresol derivatives occur naturally in various plants.
They are present in oils from jasmine, cassia, Easter lily, ylang ylang, and Yucca gloriosa flowers and in peppermint, eucalyptus and camphor. Oils from conifers, oaks and sandalwood trees also contain cresol (Fiege & Bayer, 1987). Mammalian urine and faeces naturally contain p-cresol (section 6.5). Poultry manure reportedly contains
p-cresol at an average concentration of 11.7 mg/kg (Yasuhara, 1987).
Cresols are frequently produced as metabolic intermediates in the degradation of bound phenols by soil microorganisms. They are also products of combustion and can be released to the atmosphere from natural fires associated with lightning, spontaneous combustion and volcanic activity (McKnight et al., 1982).
3.2 Anthropogenic sources
Cresols are contained in crude oil and coal tar. Therefore, the dominant anthropogenic sources of cresols are accidental and process discharge during the manufacture, use, transport and storage of cresols or associated products of the coal tar and petroleum industries. Cresols are also produced during coal gasification (Giabbai et al., 1985; Neufeld et al., 1985), coal liquefaction (Fedorak & Hrudey, 1986) and shale oil production (Snider & Manning, 1982; Dobson et al., 1985). Low levels of cresols are present in the exhaust of vehicles powered with petroleum-based fuels (Hampton et al., 1982; Johnson et al., 1989), stack emissions from municipal waste incinerators (Junk & Ford, 1980; James et al., 1984), and emissions from the incineration of vegetable materials (Liberti et al., 1983).
Cresols are also found in fly ash from coal and wood combustion (Junk & Ford, 1980; Hawthorne et al., 1988, 1989). Cigarette smoke contains cresols (Wynder & Hoffmann, 1967). In addition, the atmospheric
reaction of toluene with photochemically generated hydroxyl radicals (HO*) produces cresols (Leone et al., 1985).
3.2.1 Production levels and processes
The oldest cresol production method used in the USA is fractional distillation of coal tar. Most cresols in the USA are obtained via catalytic and thermal cracking of naphtha fractions during petroleum distillation. Since 1965, quantities of coal tar and petroleum
isolates have been insufficient to meet the rising demand for cresols in the USA. Consequently, several processes for the manufacture of the various isomers have been developed. One method of producing
o-cresol is by the methylation of phenol in the presence of catalysts. Another method uses toluene sulfonation followed by alkaline hydrolysis to produce p-cresol. Until 1972, cresols were also produced by the cymene-cresol process, where cymene
( p-isopropyltoluene) is oxidized to cymene hydroperoxide, which decomposes to cresols and acetone. This method is capable of producing p- or m-cresol from the corresponding cymene isomer.
Alkaline chlorotoluene hydrolysis is used to produce a cresol mixture with a high m-cresol content (Fiege & Bayer, 1987). The total
production of cresols in the USA, excluding production from coke oven and gas-retort ovens, was 34 400 tonnes in 1989 and 38 300 tonnes in
1990 (USITC, 1990, 1991).
According to the Toxic Release Inventory (TRI) database,
maintained by the US EPA, manufacturing and processing industries in the USA in 1987 released or transferred 52 tonnes of cresols to air, water and land, 172.5 tonnes to wastewater treatment plants, and 20.45 tonnes to off-site locations for disposal (US EPA, 1989). The TRI data may have under-estimated the actual release since only certain types of facilities were required to report.
3.2.2 Uses
A considerable amount of o-cresol is consumed directly as either a solvent or disinfectant. o-Cresol is also used as a
chemical intermediate for a variety of products, including deodorizing and odour-enhancing compounds, pharmaceuticals, fragrances,
antioxidants, dye and dye intermediates, pesticides and resins.
Recently, an increasing proportion of o-cresol has been devoted to the formulation of epoxy- o-cresol novolak resins (sealing materials for integrated circuits silicon chips). o-Cresol is also used as an additive to phenol-formaldehyde resins (Windholz et al., 1983; Fiege &
Bayer, 1987; Sax & Lewis, 1987).
p-Cresol is mainly used in the formulation of antioxidants such as 2,6-di- tert-butyl- p-cresol for lubricating oil and motor fuels, rubber, polymers, elastomers and food products. It is also used as an intermediate in the fragrance and dye industries (Windholz et al., 1983; Fiege & Bayer, 1987; Sax & Lewis, 1987).
m-Cresol, either pure or mixed with p-cresol, is important in the production of contact herbicides and insecticides. Furthermore, many flavour and fragrance compounds and several important
antioxidants are produced from m-cresol. It is also used in the manufacture of explosives (Fiege & Bayer, 1987).
Mixtures of m- and p-cresol are used as disinfectants and preservatives. Crude cresols are used as wood preservatives.
Tricresyl phosphate and diphenyl cresyl phosphate produced from m- and p-cresol mixtures are used as flame-retardant plasticizers for polyvinyl chloride and other plastics, fire-resistant hydraulic
fluids, additives for lubricants and air filter oils. Cresol mixtures condensed with formaldehyde are important for modifying phenolic
resins. Cresols are also used in paints and textiles. Mixtures of cresols are used as solvents for synthetic resin coatings such as wire enamels, metal degreasers, cutting oils and agents to remove carbon deposits from combustion engines. They are also used in ore
flotation, fibre treatment and photography (Deichmann & Keplinger, 1981; Windholz, 1983; Fiege & Bayer, 1987).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media
4.1.1 Air
The levels of cresols in the atmosphere will be regulated by the physical properties of the compounds, their chemical reactivity and by prevailing weather conditions (wind speed, precipitation, temperature inversions, etc.). The vapour pressures of cresols range from 0.13 to 0.31 mmHg (Table 2); compounds with values greater than 0.0001 mmHg should exist predominantly in the vapour phase (Eisenreich et al., 1981) as opposed to the particulate-bound phase (Cautreels & van Cauwenberghe, 1978). Photochemical attack (section 4.2) and rain scavenging (Leuenberger et al., 1985; Czuczwa et al., 1987) rapidly
remove cresols from the vapour phase, counteracting the tendency of compounds that exist in the vapour phase to be transported over long distances.
4.1.2 Water
The processes that control the transport of cresols from water and their distribution in water are volatility, values for the sorption coefficient (Koc) to suspended solids and sediment, and
bioaccumulation in aquatic organisms. The bioaccumulation of cresols in aquatic organisms is discussed in section 4.3. The volatility of a compound can be qualitatively predicted from its Henry's Law constant (H). The rate of volatilization from water is high for compounds with H values ranging from 10-2 to 10-3 atm-m3/mol, and it is very
low for compounds with H values of 10-7 atm-m3/mol or less (Lyman et al., 1990). Therefore, transport of cresols with H values of 1.26 × 10-6 to 7.92 × 10-7 atm-m3/mol from water to the atmosphere will not be significant. Furthermore, the ability of these phenolic
compounds to dissociate and to form hydrogen bonds, leading to binding with both suspended solids or sediments, will decrease the rate of volatilization even further. Since the cresols are soluble in water (see Table 2), the small amounts of cresols typically found in the aquatic environment will be present mostly in the aqueous phase.
However, transport of cresols from water to bottom sediment is possible as a result of sorption and subsequent precipitation. For hydrophobic compounds, the importance of the sorption process can usually be predicted from the Koc values. Details of Koc levels are given in section 4.1.3.
4.1.3 Soil
Koc values in soil of between 22 and 3420 have been reported (Boyd, 1982; Southworth & Keller, 1986; Koch & Nagel, 1988). The sorption of cresols to several soils correlates well with both pH and clay mineral content in soil (Artiola-Fortuny & Fuller, 1982), and several investigators reported that hydrogen bonding plays an important role in the sorption of cresols to soil (Boyd, 1982;
Southworth & Keller, 1986).
The transport of cresols from soil to the atmosphere will occur as a result of volatilization. The volatilization of cresols from soil will be directly proportional to H values and inversely
proportional to Koc. Since the H values for cresols are low and the Koc in soils capable of hydrogen bonding can be as high as 3420, volatilization will not be significant in such soils. However, some volatilization may occur due to the relatively high vapour pressure of cresols (Table 2) and to the diffusion gradient between the soil and the atmosphere. Loss of cresols by volatilization has been shown to occur from highly contaminated soils (Evangelista et al., 1990).
Another process that may transport cresols from soil to ground water is leaching. The leaching of cresols from soil will depend on the Koc. This is variable so that with values near 3000, cresols will be slightly mobile, whereas cresols in soil with Koc values in the lowest range will be highly mobile (Swann et al., 1983). The
horizontal transport of cresols from one land area to another or to surface water as a result of run-off will also occur to a certain extent, dependent among other factors on the soil Koc value.
4.2 Transformation
4.2.1 Abiotic transformation
Two abiotic transformation processes, namely reaction with
hydroxyl HO* and nitrate NO3* radicals, are most important for determining the fate of cresols in air. The rate constants for the reaction with HO* are 4.2 × 10-11, 6.4 × 10-11 and 4.7 × 10-11
cm3/molecule-sec for o-, m- and p-cresol, respectively
(Atkinson et al., 1992). It may be estimated from the range of HO*
concentrations in the lower troposphere (from below the limits of detection at 1 × 106 radicals/cm3 to a maximum of 5 × 106
radicals/cm3) (Atkinson, 1985), that the half-lives for the cresols during the daytime may range from 3 to 5 h. The major products of the reactions of HO* with cresols in the presence of nitrogen oxides are pyruvic acid, acetaldehyde, formaldehyde, peroxyacetylnitrate and nitrocresols (Atkinson et al., 1980; Grosjean, 1984, 1985). NO3* is formed in the atmosphere as a result of the reaction of nitrogen oxide with ozone and is photodecomposed quickly by sunlight (Carter et al., 1981). Therefore, the reaction of atmospheric pollutants with NO3*
can be significant only during the night. The determined rate constants for the reaction of NO3* with vapour-phase cresols are 1.37 × 10-11, 9.74 × 10-12 and 1.07 × 10-11 cm3/molecule-sec
for o-, m- and p-cresol, respectively (Carter et al., 1981;
Atkinson et al., 1992). Assuming that the average concentration of NO3* in a typical night-time urban atmosphere is 2.4 × 108
molecules/cm3, cresols are estimated to be removed from the atmosphere with half-lives of 5-10 min (Atkinson, 1985).
Abiotic reactions, such as photolysis, hydrolysis and oxidation by photolytically produced HO* and singlet oxygen, play a minor role in determining the fate of cresols in water (Smith et al., 1978; Faust & Hoigné, 1987). However, the photolysis of o- and p-cresol is accelerated in the presence of fulvic and humic materials present in water. The estimated half-life for the disappearance of p-cresol in pure water containing humic acid (9.5 mg/litre) and exposed to April sunlight at 37.5°N latitude was 3 days (Smith et al., 1978). In a polluted eutrophic Swiss lake with a dissolved organic matter
concentration of 3.1 mg/litre, the estimated natural half-lives for p- and o-cresol in the top metre as a result of exposure to June sunlight were 4.4 and 11 days, respectively (Faust & Hoigné, 1987).
The investigators concluded that photochemically produced organic peroxide radicals generated from dissolved organic matter controlled the sensitized photooxidation of cresols in the Swiss lake. In addition, laboratory experiments have shown that iron (FeOOH) and manganese (III/IV) oxides (MnOOH and MnO2), commonly found in
surface water particulate and soil, can oxidize cresols in solution particularly at low pH (< 4) (Stone, 1987). However, oxidation of cresols occurs more readily in fog and rain water due to the higher concentration of manganese and iron oxide and low pH of these waters (Stone, 1987).
Direct attack of cresols by ozone may also occur in water and follows first-order reaction kinetics: 3 moles of ozone are required to cause ring-opening of 1 mole of cresol (Zheng et al., 1993a,b). The overall rate constant for the reaction increases with increasing pH and temperature. Ozonation may be a possible remediation treatment for cresol-contaminated waters.
Photochemical reactions will only occur in the upper few
millimetres of the soil surface, and it is unlikely that photochemical attack will be an important pathway for cresol removal from soil. As in the case of water, the abiotic hydrolysis of cresols in moist soil may not be significant since there is no evidence that any soil
component is capable of accelerating this reaction. The oxidation of cresols by iron(III) and manganese (III/IV) is likely in soils that have low pH; however, laboratory or field data assessing the
importance of this reaction in determining the fate of cresols in soil are not available.
4.2.2 Biodegradation
Biotic processes, namely biodegradation, may be more important than other processes in determining the fate of cresols in water (Smith et al., 1978). Cresols degraded rapidly in aerobic
biodegradation screening and sewage treatment plant simulation studies (McKinney et al., 1956; Ludzack & Ettinger, 1960; Malaney, 1960;
Chambers et al., 1963; Tabak et al., 1964; Alexander & Lustigman, 1966; Malaney & McKinney, 1966; Young et al., 1968; Pauli & Franke, 1971; Baird et al., 1974; Pitter, 1976; Singer et al., 1979; Lund &
Rodriguez, 1984; Babeu & Vaishnav, 1987; Brown & Grady, 1990; Klecka et al., 1990). According to one screening study, the rate of aerobic biodegradation of the three isomeric cresols increased in the
following order: p- > m- > o-. While no lag time for
biodegradation was observed for m- and p-cresol, o-cresol showed a lag time of 6 days (Liu & Pacepavicius, 1990). Aerobic
biodegradation in salt water (estuarine and sea water) is slower than in fresh water, but the decrease in the rate is not enough to preclude biodegradation as an important removal pathway in salt water (Palumbo et al., 1988). Mixed and pure culture studies indicate that aerobic biodegradation of cresols proceeds by initial formation of
hydroxylation products followed by ring-opening reactions (Bayly &
Wigmore, 1973; Masunaga et al., 1983, 1986).
Biodegradation reaction rates are widely variable and depend on a number of interrelated factors or conditions of the source waters.
Results of several investigations have shown that factors such as substrate and nutrient concentration, spatial and temporal sampling, bacterial growth, biofilm formation, pH and temperature all influence reaction rates. In general, higher nutrient concentrations and
temperatures (summer versus winter) increase the biodegradation of cresols. However, degradation will decrease with increased humic acid content (Visser et al., 1977; Smith et al., 1978; Paris et al., 1983, Spain & van Veld 1983; Rogers et al., 1984; Lewis et al. 1984,1986;
Shimp & Pfaender, 1985a,b; Kollig et al., 1987; Gantzer et al., 1988;
Hwang et al. 1989).
The anaerobic biodegradation potential of cresols in aquatic media has been observed in the presence of an electron acceptor, as occurs in nitrate reduction, methanogenesis and sulfate reduction conditions (Shelton & Tiedje, 1981; Horowitz et al., 1982; Boyd et al., 1983; Fedorak & Hrudey, 1984; Bak & Widdel, 1986; Roberts et al., 1987; Battersby & Wilson, 1988, 1989; Wang et al., 1988, 1989).
Cresols biodegrade more slowly under anaerobic conditions than under aerobic conditions. While several investigators observed a lag period before the onset of anaerobic biodegradation (Suflita et al., 1988;
Battersby & Wilson, 1989; Liu & Pacepavicius, 1990), Young & Rivera (1985) observed no significant increase in the rate of p-cresol metabolism as a result of acclimation. The anaerobic biodegradation rate for cresols was p- > m- > o- (Suflita et al., 1988; Wang et al., 1988; Battersby & Wilson, 1989). Other investigators have reported that o-cresol is more biodegradable under anaerobic conditions than p-cresol. The m-cresol isomer was found to be the least biodegradable (Liu & Pacepavicius, 1990). The anaerobic biodegradation of o- and p-cresol appears to proceed metabolically by oxidation of the methyl group to produce first the corresponding hydroxybenzaldehyde and then hydroxy-benzoic acid. The hydroxybenzoic acid is then decarboxylated or dehydroxylated to produce phenol or benzaldehyde, respectively (Smolenski & Suflita, 1987; Kühn et al., 1988; Suflita et al., 1988, 1989). The metabolic pathway for
anaerobic biodegradation of m-cresol may be different from the pathway for o- and p-cresols (Suflita et al., 1989).
Pseudomonads and other bacteria contain a flavocytochrome enzyme, p-cresol methylhydroxylase (PCMH), which is capable of oxidizing p-cresol without the participation of exogenous oxygen (Hopper,
1976, 1978; Hopper & Taylor, 1977; Keat & Hopper, 1978). This enzyme catalyses the dehydrogenation and hydration of p-cresol and its
homologues to the corresponding alcohols and their further
dehydrogenation to the corresponding aldehydes or ketones. Thus, p-cresol is oxidized under this condition to p-hydroxybenzyl alcohol and then to p-hydroxybenzaldehyde. Isolation and then resolution of the flavocytochrome PCMH into subunits and
reconstitution of the enzyme were studied by Keat & Hopper (1978), McIntire et al. (1981, 1984, 1985, 1986), McIntire & Singer (1982), Shamala et al. (1985, 1986) and Koerber et al. (1985).
The biodegradation of cresols in soil under aerobic conditions is rapid. However, complete metabolism (to CO2 and H2O) of the
intermediate metabolites is slower (Medvedev & Davidov, 1981a,b;
Dobbins & Pfaender, 1988; Namkoong et al., 1988). Biodegradation is likely to control the fate of cresols in soils. In surface soils from an uncultivated grassland site, the estimated half-life for the
pseudo-first-order disappearance of the parent compound was 1.6 days for o-cresol and 0.6 days for m-cresol. It could not be
calculated for p-cresols as the concentration had fallen below the detection limits at the first sampling, which was 24 h after
initiation of the experiment (Namkoong et al., 1988). The half-lives for complete metabolism in different soils ranged from 39 days to about 1 year (Dobbins & Pfaender, 1988; Swindoll et al., 1988).
4.3 Bioaccumulation and biomagnification
The measured bioconcentration factors for o-cresol and m-cresol in aquatic organisms were 14.1 and 19.9, respectively (Freitag et al., 1982; Sabljic, 1987). There is no evidence in the literature to indicate that biotransfer of cresols via the food chain causes biomagnification of these compounds.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels
5.1.1 Air
Ambient air monitoring data for cresols are sparse. These
compounds are short-lived in the air (see section 4.2.1) unless large amounts are released over a short period of time. According to the National Ambient Volatile Organic Compounds (VOCs) Data Base, a compilation of published and unpublished air monitoring data in the USA from 1970 to 1987, the median air concentration of o-cresol at source-dominated sites was 1.59 µg/m3 (0.359 ppb) (range from below detection limit to 10.58 µg/m3, 2.394 ppb) for 32 samples (Shah &
Heyerdahl, 1989). According to the same data base, o-cresol was not detected in air samples from one urban, one rural and one remote area, and m-cresol was also not detected in air samples from one urban, one suburban, and one remote area in the USA. This data base does not contain any monitoring data for p-cresol. The concentration of
o-cresol in one sample of the ambient air near a phenolic resin factory in Japan was 179 µg/m3 (40 ppb) (Hoshika & Muto, 1978). In air samples from rooms with a fireplace, cresol concentrations around 5 mg/m3 have been detected (Risner, 1993).
5.1.2 Water
