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Pyrene
Pyrene I Mangas and E Vilanova, Universidad Miguel Hernández de Elche, Elche, Spain Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Lu Yu, volume 3, pp 571–574, Ó 2005, Elsevier Inc.
l
Name: Pyrene Chemical Abstracts Service Registry Number: 29-00-0 l Synonyms: AI3-23 977, Benzo(def)phenanthrene, b-Pyrene l Molecular Formula: C16H10 l Chemical Structure: l
be 8 h); particulate-phase pyrene will be removed from the atmosphere by wet or dry deposition. In soil, pyrene has no mobility and biodegradation occurs slowly, with estimated half-lives ranging from several weeks to years. In water, pyrene is expected to adsorb to suspended solids and sediment and volatilization from water surfaces is an important fate process. Estimated volatilization half-lives for a model river and model lake are 4.5 and 37 days, respectively. However, volatilization from water surfaces is attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 29 years if adsorption is considered.
Environmental Persistency
Background Pyrene was first isolated from coal tar, where it occurs up to 2% by weight. It is produced in a wide range of combustion conditions; for example, it is the major compound of diesel exhaust particles.
Uses Pyrene is mainly used as a starting material in the production of optical brighteners and dyes. Pyrene from coal tar has been used as a starting material for the synthesis of benzo(a)pyrene and can serve as an electron donor to increase the blackness in pencil leads. It is also used in biochemical research. Pyrene is a ubiquitous product of incomplete combustion, occurring in exhaust from motor vehicles, emissions from cigarette smoke, coal-, oil-, and wood-burning stoves, and furnaces that will result in its direct release to the environment.
Environmental Fate and Behavior Physical Properties Pyrene is a colorless solid at room temperature and it is soluble in ethanol, ethyl ether, benzene, carbon disulfide, ligroin, and toluene. It is slightly soluble in carbon tetrachloride and in organic solvents. The more relevant physical properties are shown in Table 1.
Behavior in Air, Soil, and Water Pyrene released to air exists in both the vapor and particulate phases in the atmosphere; vapor-phase pyrene will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals (the half-life for this reaction is estimated to
Encyclopedia of Toxicology, Volume 3
Environmental biodegradation occurs slowly, with estimated half-lives ranging from several weeks to years. Polycyclic aromatic hydrocarbons (PAHs) with four or less aromatic rings are degraded by microbes and are readily metabolized by multicellular organisms. For example, in a study, pyrene was degraded over a 4-week incubation period, aerobically in contaminated soil from St Louis Park, MN, Cantonment, FL, and Bozeman, MT, at 45.2, 46.5, and 0.5%, respectively. The aerobic biodegradation half-life of pyrene in sediment of freshwater ecosystems has been estimated as 34–90 weeks.
Bioaccumulation Bioconcentration in aquatic organisms is moderate to high (bioconcentration factor of 72–970 in trout).
Exposure Routes and Pathways of Human Exposure Occupational exposure to pyrene may occur through inhalation and dermal contact with this compound at workplaces where pyrene is produced, where petroleum and coal tar are used, or where combustion processes are common such as coke
Table 1
More relevant physico-chemical pyrene propertiesa
Physical property
Value
T ( C)
Melting point Boiling point Log P (octanol–water) Water solubility Vapor pressure Henry’s law constant Atmospheric OH rate constant
150.62 C 404 C 4.88 0.135 mg l 4.50 1006 mmHg 1.19 1005 atm-m3 mol1 5.00 1011 cm3 mol1 s1
25 25 25 25
a
Source: http://chem.sis.nlm.nih.gov/.
http://dx.doi.org/10.1016/B978-0-12-386454-3.00535-2
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Pyrene
plants, iron foundries, and aluminum factories and during the manufacture of dyes. General population is also exposed to pyrene; it was detected in 100% of the personal air samples in Minnesota Children’s Pesticide Exposure Study at a mean concentration of 2.1 ng m3. Exposure may arise via smoking, dermal contact, and inhalation of ambient air, particularly in areas with heavy traffic or near industrial sources, or from consuming contaminated food and drinking water. In fact, human exposures to PAHs in general are approximately 99% from dietary sources.
Main Pathways of Human Exposure Pyrene concentration in mainstream cigarette smoke is 1700–14 000 ug/100 cigarettes. Moreover, pyrene was detected in 99% of the food samples in Minnesota Children’s Pesticide Exposure Study at a mean concentration of 0.4 ug kg1. The food surveys with more concentration of pyrene are heavily smoked bacon (27 ug kg1), heavily smoked ham (35–161 ug kg1), and barbecued beef (3.2 ug kg1), but it is also detected in vegetables (lettuce (0.433 ug kg1), tomatoes (0.395 ug kg1)). The average daily intake of pyrene for women in Japan has been estimated at 0.98 ng day1.
Monitoring Data Water: The average concentration of pyrene in the groundwater near five wood treatment facilities sampled in the United States was 666 ug l1 and in undisclosed locations at concentrations of 1.6–2.5 ng l1. Pyrene was detected in the Mississippi River at concentrations of 1–15 ng l1, in eastern Ontario waters at 0.2–1.7 ng l1, and in Lake Superior at an average of 0.28 ng l1. Sediment: Pyrene was detected in the sediment of Lake Superior at a concentration of 1.76 ug g1 and of 13–266 ug g1 in other study; and in Lake Ontario at concentrations of 1.2–72.7 ug g1. Soil: Pyrene was measured in the soil at an urban roadside in Australia at a concentration of 214 ug kg1 and was detected in the soil of UK sites at Birmingham (254 ug kg1), Brisbane (214 ug kg1), Wales (63 ug kg1), and Herts (131 ug kg1). Atmosphere: The average atmospheric concentration of pyrene in London was measured as 1.90 ng m3 in winter and 0.43 ng m3 in summer. Pyrene was detected in Antarctic air at concentrations of 4.2–24.8 103 ng m3 and 5.5–50.9 103 ng m3.
Table 2
Absorption, Distribution, and Excretion Pyrene is absorbed via oral, dermal, and respiratory routes. It is highly soluble in adipose tissue and lipids and easily penetrates cellular membranes.
Metabolism It is readily metabolized by liver microsomes to trans-4,5dihydro-4,5-dihydroxypyrene, s-(4,5-dihydro-4-hydroxypyren5-yl)glutathione, 1,6-dihydroxypyrene, 1,8-dihydroxypyrene, and 1-hydroxypyrene (1-OHPy) in rats and rabbits. Two trihydroxy derivatives were also isolated following incubation of pyrene with rat liver preparations. The high water solubility of the metabolites makes them readily excretable. Urinary 1-OHPy has been used as a biomarker for environmental PAH exposure in humans.
Biological Half-Life The apparent elimination rate of C-pyrene (23 h) contained in the skin after an exposure of 4.5 h was similar to the apparent urinary excretion half-life of 1-OHPy (21 h). These values are threefold higher than the urinary excretion half-life of 1-OHPy after an intravenous administration of pyrene (0.5 mg kg1).
Mechanism of Toxicity Oxidation of the rings of pyrene is an important step in its metabolism carried out by mixed function oxidases of the liver containing cytochromes P450 and P448. Epoxide intermediates are formed from oxidation. They are very reactive and can form covalent complexes with DNA and histones, which serve as the ultimate carcinogenic form of pyrene.
Acute and Short-Term Toxicity Animal Data Exposed experimental animals have also developed excitation and muscle spasticity. Table 2 shows the nonhuman toxicity values.
Acute toxicity studiesa
Study
LD50/LC50
Mouse intraperitoneal Mouse oral
LD50: 514 mg kg1
Rat inhalation
LC50: 170 mg m3
Rat oral
LD50: 2700 mg kg1
a
Toxicokinetics
LD50: 800 mg kg1
Source: http://chem.sis.nlm.nih.gov/.
Effect
Source Prog. Mutat. Res. 1981, 1, 682.
Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity
Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59. Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59. Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59.
Pyrene
Human Data Exposure to pyrene causes irritation of skin, eyes, nose, and throat. Some unspecified teratogenic effects were noted in workers. Coal tar pitch volatiles are reported to cause bronchitis.
Chronic Toxicity (Animal/Human) Animal Data Nephropathy and decreased kidney weights were detected in a subchronic exposure assay, where male and female CD-1 mice (20/sex/group) were gavaged with 0, 75, 125, or 250 mg kg1 day1 pyrene in corn oil for 13 weeks. Based on the results of this study, the low dose (75 mg kg1 day1) was considered the no observed effect level (NOAEL) and 125 mg kg1 day1 the lowest observed effect level (LOAEL) of this study. Dermal applications of pyrene for 10 days caused hyperemia, weight loss, and hematopoietic changes; applications for 30 days produced dermatitis; and chronic effects consisted of leukocytosis and lengthened chromaxia of the leg muscle flexors. Moreover, an increase of papillomas incidence (nine papillomas were present on 6/20 surviving animals compared with four papillomas on 4/19 survivors in the control group) was detected in a subchronic study in 20 S-strain mice treated by 10 thrice-weekly applications of 8.3% pyrene solution in acetone (total dose, 0.25 g). Pyrene induces rat liver acrylamide N-hydroxylase activity and modifies the enzyme by increasing its apparent Michaelis constant (km). Goblet cell hyperplasia and cases of so-called transitional hyperplasia were observed when pyrene was implanted (in a beeswax pellet) into isogenically transplanted rat tracheas.
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embryonic mouse kidney in organ culture, compared with controls. The effects were similar but less marked than those produced by benzo(a)pyrene. Administration of two subcutaneous injections of 6 mg pyrene on days 18 and 19 of pregnancy to strain A mice did not induce an increased tumor incidence in the offspring in studies in which benzo(a)pyrene injections did have that effect.
Genotoxicity There is limited evidence that pyrene is active in short-term assays. In bacterial gene mutation tests, both positive and negative results have been reported, the protocol or evaluation criteria were critical factors in individual test verdicts. Mixed results have also been observed in mammalian assays in vitro, again with protocol and evaluation criteria being a factor in at least some of the cases. Results of mammalian cell transformation assays in a variety of cell types have not been positive. However, pyrene was positive in one study for sister chromatid exchanges (SCE) induction in cultured Chinese hamster ovary cells (CHO). Two other laboratories reported pyrene negative both for SCE and chromosome aberrations in CHO cells. Pyrene did not induce SCE in a rat liver epithelial cell system, but was positive in the L5178Y mouse lymphoma gene mutation assay. Pyrene did not induce chromosome aberrations (as detected by micronuclei) or SCE in bone marrow of several mouse strains receiving intraperitoneal injections of pyrene. Pyrene was nonmutagenic in Drosophila sex-linked recessive lethal test. Reduced keratinocyte recovery occurred following exposure of mice to pyrene and other chemicals; there was no evidence that these cytotoxic effects contributed to micronuclei scored in keratinocytes. Pyrene failed to induce micronuclei at doses from 2.5 ug to 2.5 mg per mouse.
Human Data Exposure to sun may provoke an irritating effect of pyrene on skin and lead to chronic skin discoloration.
Immunotoxicity Epidemiological studies and experiments with mouse models suggest that PAHs contained in, among others, diesel exhaust particles can promote the development of allergy. Pyrene may promote allergic diseases by inducing the production of IL-4 through induced transcription of IL-4 messenger RNA and expression of IL-4 protein in primary human T cells. The results of a study in mice suggest that pyrene contained in diesel exhaust particulates acts as an adjuvant in IgE antibody production when mice are immunized with antigens.
Reproductive Toxicity When pyrene at 4 mg per mouse was injected in sunflower oil intramuscularly everyday during the last week of gestation (into BALB/c, C3H/a, C57BI CBA F hybrids), increased survival and hyperplastic changes were seen in explants of
Carcinogenicity Pyrene is not classifiable as human carcinogen by the US Environmental Protection Agency (EPA), based on inadequate evidence of carcinogenicity in humans and inadequate or limited evidence in experimental animals. Increased incidences of lung, skin, or genitourinary cancers were observed in workers exposed to a variety of PAHs. Carcinogenicity of pyrene was tested on mouse skin in multiple studies and all studies gave negative results. Groups of 14–29 newborn male and 18–49 newborn female CD-1 mice on 1, 8, and 15 days of age received intraperitoneal injections of pyrene in dimethyl sulfoxide (DMSO) (total dose ¼ 40, 141, or 466 ug per mouse), or DMSO alone. Tumors were evaluated in animals that died spontaneously after weaning and in all remaining animals at 1 year after exposure. The middose group was initiated 10 weeks after the other groups and had a separate vehicle control. The survival rate in the high-dose groups (male and female) was 25–35%; most of the mice died between the last injection and weaning. This high mortality was not observed in the control, low-, or middose groups (the survival rates were not stated). A statistically significant increase in the incidence of liver carcinomas occurred in the middose males
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Table 3
Ecotoxicity valuesa
Species
Effect
Conditions
Pseudokirchneriella subcapitata (green algae, age < 24 h); immobilization Daphnia magna (water flea); growth rate Daphnia magna (water flea, age < 24 h, neonate); immobilization Daphnia magna (water flea, age 4–6 days); immobilization Daphnia magna (water flea, age 4–6 days, length 1.5 mm); immobilization Americamysis bahia (opossum shrimp, age 24–48 h) Americamysis bahia (opossum shrimp, age 24–48 h) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Pimephales promelas (fathead minnow, weight 0.8 g, length 5 cm) Eisenia veneta (earthworm, sexually mature organism, weight 0.8 g, length 6.2 cm) Enchytraeus crypticus (earthworm, sexually mature organism)
EC50: 894 000 ug l1 for 72 h (98% purity)
Freshwater, static
EC50: 72.7 ug l1 for 7 days (>99% purity) EC50: 67 000 ug l1 for 48 h (98% purity) EC50: 0.45 mmol m3 for 48 h (97% purity) EC50: 9 mmol m3for 48 h (95% confidence interval: 1–14 mmol m3 (97% purity) LC50: 0.89 ug l1 for 48 h LC50: 24.8 ug l1 for 48 h LC50: >2000 ug l1 for 24 h LC50: >2000 ug l1 for 48 h LC50: >2000 ug l1 for 96 h LC50: 200 ug l1 for 24 h (100% purity) LC50: 155 mg kg1 dry weight soil for 28 days
Freshwater, renewal Freshwater, static; Freshwater, static, 23 C Freshwater, static, 23 C, pH 6–7, dissolved oxygen 5–9 mg l1 Saltwater, static, 21.5 C, UV light Saltwater, static, 21.5 C, fluorescent light Saltwater, static, 21.5 C, fluorescent light Freshwater, renewal, 11.0 C, pH 6.19 Freshwater, renewal, 11.0 C, pH 6.19 Freshwater, static Direct application
LC50: >2300 mg kg1 for 21 days
Direct application
a
Source: http://chem.sis.nlm.nih.gov/.
Pyrene
(3/25) relative to their vehicle control group (0/45), but not in the high-dose males (1/14) or low-dose males (0/29) or in female mice, when compared with their respective controls. The incidences of total liver tumors (adenomas and carcinomas), lung tumors, or malignant lymphomas were not statistically significantly elevated in treated animals. The results of this 1-year experiment were not considered to be positive because of the overall lack of tumorigenic response in the short term. The induction of DNA adducts and adenomas in the lungs of strain A/J mice has been investigated following the single intraperitoneal administration of pyrene. DNA adducts were measured by 32P-postlabeling at times between 1 and 21 days following injection, while adenomas were counted at 240 days after treatment. Pyrene did not induce either DNA adducts or lung adenomas at any of the doses examined.
Clinical Management Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure. The determination of 1-OHPy in the urine of PAHexposed workers is used as biomarker. Tabaquism practically does not affect this value. Acute intoxications are unlikely but a significant exposure can occur through the skin. For immediate first aid, the affected individual should be removed from the exposure source and if the patient is not breathing, artificial respiration should be started. Do not induce vomiting and keep the patient quiet and maintain normal body temperature. Obtain medical attention. After oral exposure, two emergency treatments are possible: (1) dilution with 4–8 ounces (120–240 ml) of water or milk; (2) administer activated charcoal (usual dose: 25–100 g in adults/adolescents, 25–50 g in children (1–12 years), and 1 g kg1 in infants less than 1 year). If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury. After inhalation exposure, move the patient to fresh air, watch for signs of respiratory insufficiency, and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10–15 l min1 and monitor for pulmonary edema and treat if necessary. Treat bronchospasm with inhaled beta2-agonist and oral or parenteral corticosteroids. If acute lung injury exists, maintain ventilation and oxygenation and evaluate with frequent arterial blood gas or pulse oximetry monitoring. Early use of peep and mechanical ventilation may be needed. After eye exposure firstly irrigate exposed eyes with copious amounts of room temperature water for at least 15 min. If irritation, pain, swelling, lacrimation, or photophobia persists, the patient should be seen in a health care facility. After dermal exposure treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
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Ecotoxicology Pyrene has a moderate to high tendency to bioaccumulate in aquatic organisms from water, sediment, and food. Table 3 shows the results of some ecotoxicity studies.
Exposure Standards and Guidelines The EPA Integrated Risk Information System (IRIS) reference dose is 0.03 mg kg1 day1. The State drinking water guidelines are Florida, 210 mg l1; Minnesota, 220 mg l1; and Wisconsin, 250 mg l1. Clean Water Act requirements: For the maximum protection of human health from the potential carcinogenic effects due to exposure to pyrene, the ambient water criteria are 28.0, 2.8, and 0.28 ng l1, respectively, corresponding to the levels which may result in increment of cancer risk over the lifetime at 1 105, 1 106, and 1 107. The levels are 311, 31.1, and 3.11 ng l1, respectively, if the above estimates are made for consumption of aquatic organisms, excluding consumption of water.
Occupational Exposure Standards Occupational Safety and Health Administration Standards Permissible exposure limit: 8-h time-weighted average: 0.2 mg m3.
National Institute for Occupational Safety and Health (NIOSH) Recommendations Recommended exposure limit: 10-h time-weighted average: 0.1 mg m3 (cyclohexane-extractable fraction). NIOSH considers coal tar pitch volatiles to be potential occupational carcinogens. Immediately dangerous to life or health: 80 mg m3.
See also: Coal Tar; Benzo(a)pyrene; Polycyclic Aromatic Hydrocarbons (PAHs); The Globally Harmonized System for Classification and Labeling of the GHS.
Further Reading Hendon, L.A., Carlson, E.A., Manning, S., Brouwer, M., Mar 2008. Molecular and developmental effects of exposure to pyrene in the early life-stages of Cyprinodon variegatus. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 147 (2), 205–215. Zhang, Y., Wang, C., Huang, L., Chen, R., Chen, Y., Zuo, Z., 15 Jun 2012. Low-level pyrene exposure causes cardiac toxicity in zebrafish (Danio rerio) embryos. Aquat. Toxicol. 114–115, 119–124.
Relevant Websites http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances – European Chemicals Agency, Registered Substances. http://toxnet.nlm.nih.gov/ – Hazardous Substance Data Bank (2009) Stoddard Solvent. http://chem.sis.nlm.nih.gov/ – United States National Library of Medicine.
l
Name: Pyrene Chemical Abstracts Service Registry Number: 29-00-0 l Synonyms: AI3-23 977, Benzo(def)phenanthrene, b-Pyrene l Molecular Formula: C16H10 l Chemical Structure: l
be 8 h); particulate-phase pyrene will be removed from the atmosphere by wet or dry deposition. In soil, pyrene has no mobility and biodegradation occurs slowly, with estimated half-lives ranging from several weeks to years. In water, pyrene is expected to adsorb to suspended solids and sediment and volatilization from water surfaces is an important fate process. Estimated volatilization half-lives for a model river and model lake are 4.5 and 37 days, respectively. However, volatilization from water surfaces is attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 29 years if adsorption is considered.
Environmental Persistency
Background Pyrene was first isolated from coal tar, where it occurs up to 2% by weight. It is produced in a wide range of combustion conditions; for example, it is the major compound of diesel exhaust particles.
Uses Pyrene is mainly used as a starting material in the production of optical brighteners and dyes. Pyrene from coal tar has been used as a starting material for the synthesis of benzo(a)pyrene and can serve as an electron donor to increase the blackness in pencil leads. It is also used in biochemical research. Pyrene is a ubiquitous product of incomplete combustion, occurring in exhaust from motor vehicles, emissions from cigarette smoke, coal-, oil-, and wood-burning stoves, and furnaces that will result in its direct release to the environment.
Environmental Fate and Behavior Physical Properties Pyrene is a colorless solid at room temperature and it is soluble in ethanol, ethyl ether, benzene, carbon disulfide, ligroin, and toluene. It is slightly soluble in carbon tetrachloride and in organic solvents. The more relevant physical properties are shown in Table 1.
Behavior in Air, Soil, and Water Pyrene released to air exists in both the vapor and particulate phases in the atmosphere; vapor-phase pyrene will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals (the half-life for this reaction is estimated to
Encyclopedia of Toxicology, Volume 3
Environmental biodegradation occurs slowly, with estimated half-lives ranging from several weeks to years. Polycyclic aromatic hydrocarbons (PAHs) with four or less aromatic rings are degraded by microbes and are readily metabolized by multicellular organisms. For example, in a study, pyrene was degraded over a 4-week incubation period, aerobically in contaminated soil from St Louis Park, MN, Cantonment, FL, and Bozeman, MT, at 45.2, 46.5, and 0.5%, respectively. The aerobic biodegradation half-life of pyrene in sediment of freshwater ecosystems has been estimated as 34–90 weeks.
Bioaccumulation Bioconcentration in aquatic organisms is moderate to high (bioconcentration factor of 72–970 in trout).
Exposure Routes and Pathways of Human Exposure Occupational exposure to pyrene may occur through inhalation and dermal contact with this compound at workplaces where pyrene is produced, where petroleum and coal tar are used, or where combustion processes are common such as coke
Table 1
More relevant physico-chemical pyrene propertiesa
Physical property
Value
T ( C)
Melting point Boiling point Log P (octanol–water) Water solubility Vapor pressure Henry’s law constant Atmospheric OH rate constant
150.62 C 404 C 4.88 0.135 mg l 4.50 1006 mmHg 1.19 1005 atm-m3 mol1 5.00 1011 cm3 mol1 s1
25 25 25 25
a
Source: http://chem.sis.nlm.nih.gov/.
http://dx.doi.org/10.1016/B978-0-12-386454-3.00535-2
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Pyrene
plants, iron foundries, and aluminum factories and during the manufacture of dyes. General population is also exposed to pyrene; it was detected in 100% of the personal air samples in Minnesota Children’s Pesticide Exposure Study at a mean concentration of 2.1 ng m3. Exposure may arise via smoking, dermal contact, and inhalation of ambient air, particularly in areas with heavy traffic or near industrial sources, or from consuming contaminated food and drinking water. In fact, human exposures to PAHs in general are approximately 99% from dietary sources.
Main Pathways of Human Exposure Pyrene concentration in mainstream cigarette smoke is 1700–14 000 ug/100 cigarettes. Moreover, pyrene was detected in 99% of the food samples in Minnesota Children’s Pesticide Exposure Study at a mean concentration of 0.4 ug kg1. The food surveys with more concentration of pyrene are heavily smoked bacon (27 ug kg1), heavily smoked ham (35–161 ug kg1), and barbecued beef (3.2 ug kg1), but it is also detected in vegetables (lettuce (0.433 ug kg1), tomatoes (0.395 ug kg1)). The average daily intake of pyrene for women in Japan has been estimated at 0.98 ng day1.
Monitoring Data Water: The average concentration of pyrene in the groundwater near five wood treatment facilities sampled in the United States was 666 ug l1 and in undisclosed locations at concentrations of 1.6–2.5 ng l1. Pyrene was detected in the Mississippi River at concentrations of 1–15 ng l1, in eastern Ontario waters at 0.2–1.7 ng l1, and in Lake Superior at an average of 0.28 ng l1. Sediment: Pyrene was detected in the sediment of Lake Superior at a concentration of 1.76 ug g1 and of 13–266 ug g1 in other study; and in Lake Ontario at concentrations of 1.2–72.7 ug g1. Soil: Pyrene was measured in the soil at an urban roadside in Australia at a concentration of 214 ug kg1 and was detected in the soil of UK sites at Birmingham (254 ug kg1), Brisbane (214 ug kg1), Wales (63 ug kg1), and Herts (131 ug kg1). Atmosphere: The average atmospheric concentration of pyrene in London was measured as 1.90 ng m3 in winter and 0.43 ng m3 in summer. Pyrene was detected in Antarctic air at concentrations of 4.2–24.8 103 ng m3 and 5.5–50.9 103 ng m3.
Table 2
Absorption, Distribution, and Excretion Pyrene is absorbed via oral, dermal, and respiratory routes. It is highly soluble in adipose tissue and lipids and easily penetrates cellular membranes.
Metabolism It is readily metabolized by liver microsomes to trans-4,5dihydro-4,5-dihydroxypyrene, s-(4,5-dihydro-4-hydroxypyren5-yl)glutathione, 1,6-dihydroxypyrene, 1,8-dihydroxypyrene, and 1-hydroxypyrene (1-OHPy) in rats and rabbits. Two trihydroxy derivatives were also isolated following incubation of pyrene with rat liver preparations. The high water solubility of the metabolites makes them readily excretable. Urinary 1-OHPy has been used as a biomarker for environmental PAH exposure in humans.
Biological Half-Life The apparent elimination rate of C-pyrene (23 h) contained in the skin after an exposure of 4.5 h was similar to the apparent urinary excretion half-life of 1-OHPy (21 h). These values are threefold higher than the urinary excretion half-life of 1-OHPy after an intravenous administration of pyrene (0.5 mg kg1).
Mechanism of Toxicity Oxidation of the rings of pyrene is an important step in its metabolism carried out by mixed function oxidases of the liver containing cytochromes P450 and P448. Epoxide intermediates are formed from oxidation. They are very reactive and can form covalent complexes with DNA and histones, which serve as the ultimate carcinogenic form of pyrene.
Acute and Short-Term Toxicity Animal Data Exposed experimental animals have also developed excitation and muscle spasticity. Table 2 shows the nonhuman toxicity values.
Acute toxicity studiesa
Study
LD50/LC50
Mouse intraperitoneal Mouse oral
LD50: 514 mg kg1
Rat inhalation
LC50: 170 mg m3
Rat oral
LD50: 2700 mg kg1
a
Toxicokinetics
LD50: 800 mg kg1
Source: http://chem.sis.nlm.nih.gov/.
Effect
Source Prog. Mutat. Res. 1981, 1, 682.
Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity Conjunctive irritation: eye, behavioral: excitement, behavioral: muscle contraction or spasticity
Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59. Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59. Gigiena Truda i Professional’nye Zabolevaniya. Labor Hyg. Occup. Dis. 1971, 15 (2), 59.
Pyrene
Human Data Exposure to pyrene causes irritation of skin, eyes, nose, and throat. Some unspecified teratogenic effects were noted in workers. Coal tar pitch volatiles are reported to cause bronchitis.
Chronic Toxicity (Animal/Human) Animal Data Nephropathy and decreased kidney weights were detected in a subchronic exposure assay, where male and female CD-1 mice (20/sex/group) were gavaged with 0, 75, 125, or 250 mg kg1 day1 pyrene in corn oil for 13 weeks. Based on the results of this study, the low dose (75 mg kg1 day1) was considered the no observed effect level (NOAEL) and 125 mg kg1 day1 the lowest observed effect level (LOAEL) of this study. Dermal applications of pyrene for 10 days caused hyperemia, weight loss, and hematopoietic changes; applications for 30 days produced dermatitis; and chronic effects consisted of leukocytosis and lengthened chromaxia of the leg muscle flexors. Moreover, an increase of papillomas incidence (nine papillomas were present on 6/20 surviving animals compared with four papillomas on 4/19 survivors in the control group) was detected in a subchronic study in 20 S-strain mice treated by 10 thrice-weekly applications of 8.3% pyrene solution in acetone (total dose, 0.25 g). Pyrene induces rat liver acrylamide N-hydroxylase activity and modifies the enzyme by increasing its apparent Michaelis constant (km). Goblet cell hyperplasia and cases of so-called transitional hyperplasia were observed when pyrene was implanted (in a beeswax pellet) into isogenically transplanted rat tracheas.
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embryonic mouse kidney in organ culture, compared with controls. The effects were similar but less marked than those produced by benzo(a)pyrene. Administration of two subcutaneous injections of 6 mg pyrene on days 18 and 19 of pregnancy to strain A mice did not induce an increased tumor incidence in the offspring in studies in which benzo(a)pyrene injections did have that effect.
Genotoxicity There is limited evidence that pyrene is active in short-term assays. In bacterial gene mutation tests, both positive and negative results have been reported, the protocol or evaluation criteria were critical factors in individual test verdicts. Mixed results have also been observed in mammalian assays in vitro, again with protocol and evaluation criteria being a factor in at least some of the cases. Results of mammalian cell transformation assays in a variety of cell types have not been positive. However, pyrene was positive in one study for sister chromatid exchanges (SCE) induction in cultured Chinese hamster ovary cells (CHO). Two other laboratories reported pyrene negative both for SCE and chromosome aberrations in CHO cells. Pyrene did not induce SCE in a rat liver epithelial cell system, but was positive in the L5178Y mouse lymphoma gene mutation assay. Pyrene did not induce chromosome aberrations (as detected by micronuclei) or SCE in bone marrow of several mouse strains receiving intraperitoneal injections of pyrene. Pyrene was nonmutagenic in Drosophila sex-linked recessive lethal test. Reduced keratinocyte recovery occurred following exposure of mice to pyrene and other chemicals; there was no evidence that these cytotoxic effects contributed to micronuclei scored in keratinocytes. Pyrene failed to induce micronuclei at doses from 2.5 ug to 2.5 mg per mouse.
Human Data Exposure to sun may provoke an irritating effect of pyrene on skin and lead to chronic skin discoloration.
Immunotoxicity Epidemiological studies and experiments with mouse models suggest that PAHs contained in, among others, diesel exhaust particles can promote the development of allergy. Pyrene may promote allergic diseases by inducing the production of IL-4 through induced transcription of IL-4 messenger RNA and expression of IL-4 protein in primary human T cells. The results of a study in mice suggest that pyrene contained in diesel exhaust particulates acts as an adjuvant in IgE antibody production when mice are immunized with antigens.
Reproductive Toxicity When pyrene at 4 mg per mouse was injected in sunflower oil intramuscularly everyday during the last week of gestation (into BALB/c, C3H/a, C57BI CBA F hybrids), increased survival and hyperplastic changes were seen in explants of
Carcinogenicity Pyrene is not classifiable as human carcinogen by the US Environmental Protection Agency (EPA), based on inadequate evidence of carcinogenicity in humans and inadequate or limited evidence in experimental animals. Increased incidences of lung, skin, or genitourinary cancers were observed in workers exposed to a variety of PAHs. Carcinogenicity of pyrene was tested on mouse skin in multiple studies and all studies gave negative results. Groups of 14–29 newborn male and 18–49 newborn female CD-1 mice on 1, 8, and 15 days of age received intraperitoneal injections of pyrene in dimethyl sulfoxide (DMSO) (total dose ¼ 40, 141, or 466 ug per mouse), or DMSO alone. Tumors were evaluated in animals that died spontaneously after weaning and in all remaining animals at 1 year after exposure. The middose group was initiated 10 weeks after the other groups and had a separate vehicle control. The survival rate in the high-dose groups (male and female) was 25–35%; most of the mice died between the last injection and weaning. This high mortality was not observed in the control, low-, or middose groups (the survival rates were not stated). A statistically significant increase in the incidence of liver carcinomas occurred in the middose males
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Table 3
Ecotoxicity valuesa
Species
Effect
Conditions
Pseudokirchneriella subcapitata (green algae, age < 24 h); immobilization Daphnia magna (water flea); growth rate Daphnia magna (water flea, age < 24 h, neonate); immobilization Daphnia magna (water flea, age 4–6 days); immobilization Daphnia magna (water flea, age 4–6 days, length 1.5 mm); immobilization Americamysis bahia (opossum shrimp, age 24–48 h) Americamysis bahia (opossum shrimp, age 24–48 h) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Oncorhynchus mykiss (rainbow trout, weight 3.17 g, length 6.2 cm) Pimephales promelas (fathead minnow, weight 0.8 g, length 5 cm) Eisenia veneta (earthworm, sexually mature organism, weight 0.8 g, length 6.2 cm) Enchytraeus crypticus (earthworm, sexually mature organism)
EC50: 894 000 ug l1 for 72 h (98% purity)
Freshwater, static
EC50: 72.7 ug l1 for 7 days (>99% purity) EC50: 67 000 ug l1 for 48 h (98% purity) EC50: 0.45 mmol m3 for 48 h (97% purity) EC50: 9 mmol m3for 48 h (95% confidence interval: 1–14 mmol m3 (97% purity) LC50: 0.89 ug l1 for 48 h LC50: 24.8 ug l1 for 48 h LC50: >2000 ug l1 for 24 h LC50: >2000 ug l1 for 48 h LC50: >2000 ug l1 for 96 h LC50: 200 ug l1 for 24 h (100% purity) LC50: 155 mg kg1 dry weight soil for 28 days
Freshwater, renewal Freshwater, static; Freshwater, static, 23 C Freshwater, static, 23 C, pH 6–7, dissolved oxygen 5–9 mg l1 Saltwater, static, 21.5 C, UV light Saltwater, static, 21.5 C, fluorescent light Saltwater, static, 21.5 C, fluorescent light Freshwater, renewal, 11.0 C, pH 6.19 Freshwater, renewal, 11.0 C, pH 6.19 Freshwater, static Direct application
LC50: >2300 mg kg1 for 21 days
Direct application
a
Source: http://chem.sis.nlm.nih.gov/.
Pyrene
(3/25) relative to their vehicle control group (0/45), but not in the high-dose males (1/14) or low-dose males (0/29) or in female mice, when compared with their respective controls. The incidences of total liver tumors (adenomas and carcinomas), lung tumors, or malignant lymphomas were not statistically significantly elevated in treated animals. The results of this 1-year experiment were not considered to be positive because of the overall lack of tumorigenic response in the short term. The induction of DNA adducts and adenomas in the lungs of strain A/J mice has been investigated following the single intraperitoneal administration of pyrene. DNA adducts were measured by 32P-postlabeling at times between 1 and 21 days following injection, while adenomas were counted at 240 days after treatment. Pyrene did not induce either DNA adducts or lung adenomas at any of the doses examined.
Clinical Management Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure. The determination of 1-OHPy in the urine of PAHexposed workers is used as biomarker. Tabaquism practically does not affect this value. Acute intoxications are unlikely but a significant exposure can occur through the skin. For immediate first aid, the affected individual should be removed from the exposure source and if the patient is not breathing, artificial respiration should be started. Do not induce vomiting and keep the patient quiet and maintain normal body temperature. Obtain medical attention. After oral exposure, two emergency treatments are possible: (1) dilution with 4–8 ounces (120–240 ml) of water or milk; (2) administer activated charcoal (usual dose: 25–100 g in adults/adolescents, 25–50 g in children (1–12 years), and 1 g kg1 in infants less than 1 year). If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury. After inhalation exposure, move the patient to fresh air, watch for signs of respiratory insufficiency, and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10–15 l min1 and monitor for pulmonary edema and treat if necessary. Treat bronchospasm with inhaled beta2-agonist and oral or parenteral corticosteroids. If acute lung injury exists, maintain ventilation and oxygenation and evaluate with frequent arterial blood gas or pulse oximetry monitoring. Early use of peep and mechanical ventilation may be needed. After eye exposure firstly irrigate exposed eyes with copious amounts of room temperature water for at least 15 min. If irritation, pain, swelling, lacrimation, or photophobia persists, the patient should be seen in a health care facility. After dermal exposure treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
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Ecotoxicology Pyrene has a moderate to high tendency to bioaccumulate in aquatic organisms from water, sediment, and food. Table 3 shows the results of some ecotoxicity studies.
Exposure Standards and Guidelines The EPA Integrated Risk Information System (IRIS) reference dose is 0.03 mg kg1 day1. The State drinking water guidelines are Florida, 210 mg l1; Minnesota, 220 mg l1; and Wisconsin, 250 mg l1. Clean Water Act requirements: For the maximum protection of human health from the potential carcinogenic effects due to exposure to pyrene, the ambient water criteria are 28.0, 2.8, and 0.28 ng l1, respectively, corresponding to the levels which may result in increment of cancer risk over the lifetime at 1 105, 1 106, and 1 107. The levels are 311, 31.1, and 3.11 ng l1, respectively, if the above estimates are made for consumption of aquatic organisms, excluding consumption of water.
Occupational Exposure Standards Occupational Safety and Health Administration Standards Permissible exposure limit: 8-h time-weighted average: 0.2 mg m3.
National Institute for Occupational Safety and Health (NIOSH) Recommendations Recommended exposure limit: 10-h time-weighted average: 0.1 mg m3 (cyclohexane-extractable fraction). NIOSH considers coal tar pitch volatiles to be potential occupational carcinogens. Immediately dangerous to life or health: 80 mg m3.
See also: Coal Tar; Benzo(a)pyrene; Polycyclic Aromatic Hydrocarbons (PAHs); The Globally Harmonized System for Classification and Labeling of the GHS.
Further Reading Hendon, L.A., Carlson, E.A., Manning, S., Brouwer, M., Mar 2008. Molecular and developmental effects of exposure to pyrene in the early life-stages of Cyprinodon variegatus. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 147 (2), 205–215. Zhang, Y., Wang, C., Huang, L., Chen, R., Chen, Y., Zuo, Z., 15 Jun 2012. Low-level pyrene exposure causes cardiac toxicity in zebrafish (Danio rerio) embryos. Aquat. Toxicol. 114–115, 119–124.
Relevant Websites http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances – European Chemicals Agency, Registered Substances. http://toxnet.nlm.nih.gov/ – Hazardous Substance Data Bank (2009) Stoddard Solvent. http://chem.sis.nlm.nih.gov/ – United States National Library of Medicine.