The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for BROMOFORM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION
2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS
3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY
4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

May 1995

Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.

Prepared for: OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM

*Managed by Lockheed Martin Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Bromoform (CAS No. 75-25-2), also referred to as tribromomethane, is a halogenated aliphatic hydrocarbon with a molecular formula of CHBr3 (Budavari et al., 1989). Bromoform is formed as a byproduct during water chlorination when chlorine reacts with endogenous organic materials such as humic and fulvic acid and bromide ions. The principal route of human exposure is from the ingestion of contaminated drinking water (ATSDR, 1990).

Bromoform is readily absorbed from the gastrointestinal tract (Mink et al., 1986) and, by analogy to related compounds, is expected to be absorbed from the respiratory tract. It is distributed to various tissues, with highest levels in adipose tissue and blood (Parra et al., 1986). Bromoform is metabolized in the liver by cytochrome P-450 oxidases; carbon monoxide and carbon dioxide are the primary metabolites (Stevens and Anders, 1979, 1981; Ahmed et al., 1977). Bromoform and its metabolites are excreted primarily through the lungs and to some extent in the urine (Mink et al., 1986).

In humans, accidental ingestion of bromoform has led to listlessness, headache, and vertigo and at higher doses to central nervous system depression, coma, and death. The estimated lethal dose for a 10- to 20-kg child is 250 to 500 mg/kg. Exposure to bromoform vapor has caused irritation of the respiratory tract, pharynx, and larynx, as well as lacrimation and salivation (von Oettingen, 1955).

In animals, the liver, kidneys, and central nervous system are the primary target organs for bromoform toxicity. The principal cause of death following acute oral exposure is central nervous system depression (Chu et al., 1980). An oral dose of 1 g/kg has produced ataxia, sedation, and anesthesia within 30 minutes in mice (Bowman et al., 1978) and oral LD50 values for rodents range from 1.14 to 1.55 g/kg (Chu et al., 1980; Bowman et al. 1978). Subchronic and chronic oral exposures (100 mg/kg by gavage for 13 weeks or 2 years) have caused lethargy in rats (NTP, 1989). Hepatic effects observed in rats and/or mice following subchronic (14-90 days) or chronic (2-year) exposure to bromoform at oral doses ranging from 50 to 200 mg/kg/day include vacuolization of hepatocytes, fat accumulation, liver enzyme changes, and increased liver weight (NTP, 1989; Chu et al., 1982; Munson et al., 1982). Kidney effects, characterized by histopathologic changes in the epithelial tubules and glomeruli and altered enzyme levels, were seen in mice exposed to bromoform by gavage at doses of >=145 mg/kg/day for 14 days (Condie et al., 1983). Additional effects following oral administration of bromoform include immune depression in mice treated with 250 mg/kg/day for 14 days (Munson et al., 1982) and fetotoxic effects (minor skeletal abnormalities) in rats treated with 100 mg/kg/day during gestation (Ruddick et al., 1983).

Acute inhalation exposure may produce severe central nervous system depression in animals. Inhalation of >=7000 ppm bromoform has caused deep anesthesia in dogs after 8 minutes and death after 1 hour (ACGIH, 1991). Central nervous system effects were also observed in rabbits exposed to 240 ppm for 10 days (Dykan, 1964), and impaired liver and kidney function has been reported in rats following exposure to 24 ppm for 2 months (Dykan, 1962). Bromoform is moderately irritating to rabbit skin and eyes (Torkelson, 1994).

Based on liver lesions seen in rats in a 13-week gavage study, an oral reference dose (RfD) of 2.00E-02 mg/kg/day was derived for chronic exposure (EPA, 1995a) and 2.00E-01 mg/kg/day for subchronic exposure to bromoform (EPA, 1995b). An inhalation reference concentration (RfC) has not been calculated for bromoform.

The epidemiological evidence for an association between ingestion of chlorinated drinking water containing bromoform and increased cancer risk is inadequate (EPA, 1989). One long-term oral study and a lung tumor assay provide evidence of carcinogenicity for bromoform in animals. An increased incidence of intestinal tumors (adenomatous polyps and adenocarcinomas) was seen in female rats receiving 200 mg/kg/day for 2 years (NTP, 1989), and an increased incidence of lung tumors was seen in male mice administered intraperitoneal injections of 4-100 mg/kg (3 times weekly for a total of 18-24 injections) of bromoform (Theiss et al., 1977).

Based on EPA guidelines, bromoform was assigned to weight-of-evidence group B2, probable human carcinogen (EPA, 1995a). For oral exposure, the slope factor and unit risk are 7.90E-03 (mg/kg/day)-1 and 2.3E-07 (ug/L) -1 (EPA, 1995a), and for inhalation exposure, the slope factor and unit risk are 3.90E-03 (mg/kg/day)-1 (EPA, 1995b) and 1.10E-06 (ug/m3)-1, respectively (EPA, 1995a).

1. INTRODUCTION

Bromoform (CAS No. 75-25-2), also referred to as tribromomethane, is a halogenated aliphatic hydrocarbon with a molecular formula of CHBr3 and a molecular weight of 252.77. It has a boiling point of 149-150C, a melting point of 7.5C, and a density of 1.6005 g/mL at 15C (Budavari et al., 1989). Bromoform is a colorless, heavy liquid with an odor and taste similar to chloroform. It is sparingly soluble in water but is soluble in ethanol, ethyl ether, benzene, solvent naphtha, and fixed and volatile oils. It is produced commercially from chloroform by replacement of chloride by reaction with anhydrous aluminum bromide, treatment with bromine and aluminum, or reaction with hydrogen bromide in the presence of an aluminum halide catalyst (EPA, 1989). Bromoform is used as an intermediate in organic synthesis; in gauge fluids; as a solvent for waxes, greases, and oils; as an ingredient in fire-resistant chemicals; and as a heavy-dense liquid in separating mixtures of chemicals (EPA, 1989). In addition, it has been used formerly in pharmaceuticals as a sedative and antitussive (NTP, 1989).

Bromoform is formed as a byproduct during water chlorination when chlorine reacts with endogenous organic materials such as humic and fulvic acid and bromide ions. The principal route of human exposure is from the ingestion of contaminated drinking water. Bromoform volatilizes from water to air, and in the atmosphere, it is expected to be relatively stable, with a half-life of about 1 to 2 months (ATSDR, 1990). In soil, bromoform is moderately to highly mobile and is expected to leach into groundwater (EPA, 1989). Bromoform is not easily biodegradable under aerobic conditions. It has been found at 13 hazardous waste sites on the National Priority List (NPL) in the United States (ATSDR, 1990).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Gastrointestinal absorption of bromoform was determined in rats and mice by Mink et al. (1986) following gavage administration of a single dose (100 mg/kg for rats and 150 mg/kg for mice). Excretion data indicate that absorption occurred rapidly and that total gastrointestinal absorption was at least 76% for rats and 62% for mice.

No studies were found regarding the absorption of bromoform in humans or animals following inhalation exposure. By analogy to related halomethanes such as chloroform, it is expected that bromoform would be readily absorbed by the lungs. Systemic effects seen in experimental animals following inhalation exposure also indicate that absorption occurs from the respiratory tract. According to von Oettingen (1955), bromoform is absorbed to some extent through the skin.

2.2 DISTRIBUTION

Bromoform was identified in the liver, kidney, brain, lungs, and stomach/intestines of a child who died following accidental ingestion of bromoform (von Oettingen, 1955).

Bromoform was distributed rapidly to tissues and organs of rats following a single gavage dose (2-16 mg/kg), with highest levels detected in adipose tissue and blood (Parra et al., 1986). Lower levels were found in several other organs including kidneys, brain, and liver. Fifteen minutes after treatment, the levels in fat were about one order of magnitude lower than those in blood. The levels in the liver were below the detection limit after 1 hour, presumably because metabolism of bromoform occurred rapidly in this organ. Mink et al. (1986) determined that only 1-2% of a single gavage dose was retained in soft tissues of rats 8 hours after dosing. Measurable levels of radiolabel were found in the brain, kidneys, liver, lungs, muscle, pancreas, stomach, thymus, and urinary bladder. A similar tissue distribution was observed in mice except that blood contained approximately 10% of the administered dose. The half-life of bromoform was 0.8 hours in rats and 8 hours in mice.

2.3 METABOLISM

Bromoform can be metabolized via tribromomethanol to carbon monoxide by a cytochrome 450 oxidase system in rat liver microsomal fraction (Stevens and Anders, 1979). Sulfhydryl compounds such as glutathione increase the rate of formation of carbon monoxide from bromoform (Ahmed et al., 1977). The glutathione-dependent production of carbon monoxide is part of the detoxification pathway for bromoform as well as for halomethanes in general (Stevens and Anders 1981). The overall metabolic pathway includes formation of dibromocarbonyl, a highly reactive intermediate, that may undergo a number of reactions including hydrolysis to yield carbon dioxide, reaction with glutathione to form carbon monoxide, and formation of covalent adducts with cellular nucleophiles (ATSDR, 1990). Dibromocarbonyl has been suggested as an intermediate responsible for bromoform-induced hepatotoxicity (NTP, 1989). Bromoform can also be metabolized through a reductive pathway that produces free radical intermediates (EPA, 1989).

2.4 EXCRETION

No studies were located regarding the excretion of bromoform by humans. In rats and mice treated orally with a single dose of radiolabeled bromoform, elimination occurred primarily through the lungs in expired air within 8 hours of dosing (Mink et al., 1986). Rats excreted approximately 4% of the total dose as CO2 and 70% as unmetabolized compound, while mice eliminated 40% as CO2 and 6% as unmetabolized parent compound, indicating that mice metabolize bromoform more extensively than rats. The urine of rats and mice contained <5% of the radiolabel after 8 hours and <10% after 36-48 hours. Lucas (1928) reported that rabbits injected rectally with a bromoform/olive oil mixture excreted 0.3% to 1.2% of the administered dose (as bromine) in the urine.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

In the early 1900s, bromoform was administered as a sedative to children suffering from whooping cough, and several deaths resulted from accidental overdoses (von Oettingen, 1955). The principal clinical signs in the fatal cases were central nervous system depression with coma and loss of reflexes. Death was usually due to respiratory failure. Although the doses were not quantified, it was estimated that 250 to 500 mg/kg would be fatal for a 10- to 20-kg child. Smaller doses have led to listlessness, headache, and vertigo.

3.1.1.2 Animal

Oral LD50 values for bromoform are 1388 and 1147 mg/kg for male and female rats, respectively (Chu et al., 1980), and 1400 and 1550 mg/kg for male and female mice, respectively (Bowman et al., 1978). The principal cause of death in laboratory animals following acute oral exposure is central nervous system depression. Clinical signs recorded in rats included piloerection, sedation, flaccid muscle tone, ataxia, prostration, and hypothermia. Enlarged livers and kidneys were observed as well (Chu et al., 1980). At doses of 1000 mg/kg, ataxia, sedation, and anesthesia occurred in mice within 60 minutes, with sedation persisting for about 4 hours (Bowman et al., 1978). In rats, a single gavage dose of 1000 mg/kg produced reductions in liver cytochrome P-450 content and aminolevulinic acid-dehydratase activity and increases in porphyrin content, suggesting disturbances in hepatic heme metabolism (Moody and Smuckler, 1986). In a screening test of motor performance with mice, Balster and Borcelleca (1982) determined an ED50 of 500 mg/kg for acute effects.

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of bromoform in humans was not available.

3.1.2.2 Animal

In a gavage study, F344/N rats and B6C3F1 mice were treated 5 times weekly for 13 weeks with bromoform at doses of 0, 12, 25, 50, 100, or 200 mg/kg (rats) or 0, 25, 50, 100, 200, or 400 mg/kg (mice) (NTP, 1989). All male rats treated with 100 or 200 mg/kg and all female rats treated with 200 mg/kg were lethargic. Dose-related increases of cytoplasmic vacuolization of hepatocytes were observed in males of both species but not in females. Chu et al. (1982) reported that administration of 5, 50, 500, or 2500 ppm bromoform in drinking water for 90 days caused no adverse effects in male and female Sprague-Dawley rats at 5 or 50 ppm. Exposure to 500 or 2500 ppm produced mild histological changes in the liver and thyroid that were not evident 90 days after cessation of exposure.

Munson et al. (1982) administered bromoform to male and female mice by gavage at daily doses of 50, 125, or 250 mg/kg/day for 14 days. Several indexes of humoral and cellular immunity were depressed in male but not in female mice exposed to the highest dose. In addition, liver weights and serum glutamate oxaloacetate transaminase (SGOT) levels were increased and serum glucose and blood urea nitrogen (BUN) levels were decreased in the high-dose animals. In a similar study, Condie et al. (1983) administered 72, 145, or 289 mg/kg/day of bromoform by gavage to CD-1 mice for 14 days. BUN levels and serum creatinine values were not altered, but serum glutamate-pyruvate transaminase (SGPT) levels were elevated in high-dose animals. Histological changes were seen in the kidneys and liver in the mid- and high-dose groups and included hyperplasia of tubular epithelial cells and hypertrophy and degenerative changes of the glomeruli in the kidney and centrilobular cytoplasmic pallor and slight focal inflammation of the liver.

Balster and Borcelleca (1982) reported effects on operant behavior in mice treated by gavage with 100 or 400 mg/kg bromoform for 60 days.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic toxicity of bromoform in humans following oral exposure was not available.

3.1.3.2 Animal

Groups of F344/N rats and B6C3F1 mice were administered bromoform in corn oil by gavage at doses of 0, 100, or 200 mg/kg (male and female rats and female mice) or at doses of 0, 50, or 100 mg/kg (male mice), 5 days/week for 2 years (NTP, 1989). Decreased survival was seen in high-dose male rats compared with controls. The body weights of low- and high-dose males and high-dose females were lower than those of controls by the end of the study. Clinical signs of toxicity included lethargy in both sexes and aggressiveness in males. Histopathologic examination revealed fatty liver changes in both sexes of treated rats, increased mixed cell foci and decreased basophilic foci in females, and necrosis of the liver in high-dose males. Forestomach ulcers, chronic inflammation of the lungs, and squamous metaplasia of the prostate gland also were seen in male rats. The inflammatory changes in the lungs may have been secondary as a result of an SDA virus infection, and forestomach ulcers may have been due to a direct irritating effect of the chemical.

In the study with mice, decreased survival was seen in low- and high-dose female mice compared with controls (NTP, 1989). The body weights of males were comparable to controls, whereas the body weights of dosed females were lower than those of controls. No clinical signs of toxicity were observed. Histopathologic examination revealed increased incidences of hyperplasia of the glandular stomach in low- and high-dose males, cytoplasmic vacuolization of hepatocytes in low- and high-dose females, and thyroid follicular cell hyperplasia in high-dose females.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Information on the developmental and reproductive toxicity of bromoform in humans following oral exposure was not available.

3.1.4.2 Animal

Ruddick et al. (1983) administered 0, 50, 100, or 200 mg/kg of bromoform by gavage to rats on days 6-15 of gestation. An increased incidence of minor skeletal abnormalities, including appearance of a 14th rib, intraparietal deviations, and delayed ossification of sternebrae, was seen in developing fetuses at 100 and 200 mg/kg.

3.1.5 Reference Dose

3.1.5.1 Subchronic

  • ORAL RfD: 2.00E-01 (mg/kg/day) (EPA, 1995b)
  • NOAEL: 17.9 mg/kg/day
  • UNCERTAINTY FACTOR: 100
  • PRINCIPAL STUDY: NTP, 1989
  • COMMENTS: The subchronic RfC is based on the same study as the chronic RfD. An uncertainty factor of 10 each was applied for interspecies variation and for protection of sensitive populations (EPA, 1995b).

3.1.5.2 Chronic

  • ORAL RfD: 2.00E-02 (mg/kg/day) (EPA, 1995a)
  • NOAEL: 17.9 mg/kg/day
  • LOAEL: 35.7 mg/kg/day
  • UNCERTAINTY FACTOR: 1000
  • CONFIDENCE: Study: Medium Data Base: Medium RfD: Medium
  • VERIFICATION DATE: 8/13/87
  • PRINCIPAL STUDY: NTP, 1989
  • COMMENTS: The RfD is based on hepatic lesions seen in male rats treated by gavage with bromoform for 13 weeks. An uncertainty factor of 10 each was applied for use of a subchronic assay, for interspecies variation, and for protection of sensitive populations (EPA, 1995a).

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Exposure to bromoform vapor has caused irritation of the respiratory tract, pharynx, and larynx, as well as lacrimation and salivation (von Oettingen, 1955).

3.2.1.2 Animal

An inhalation LCLO of 4500 mg/m3 was reported for rats exposed to bromoform for 4 hours (ACGIH, 1991). Dogs exposed to >=7000 ppm became deeply anesthetized after 8 minutes and died after a 1-hour exposure (ACGIH, 1991). A single inhalation exposure (duration not reported) to 1070-1260 ppm bromoform produced central nervous system effects in rabbits and exposure to 240 ppm for 10 days produced central nervous system effects as well as dystrophic and vascular changes in the liver and kidneys in rats (Dykan, 1964). Severe central nervous system depression was observed in dogs and guinea pigs following acute exposure to "very high" concentrations of bromoform (Graham, 1915). Clinical signs included sleep, deep sedation, and narcosis. Onset of central nervous system depression was rapid and transient, disappearing within a day following cessation of exposure.

3.2.2 Subchronic Toxicity

3.2.2.1 Human

Information on the subchronic toxicity of bromoform in humans following inhalation exposure was not available.

3.2.1.2 Animal

Hepatic changes (decreased blood clotting and impaired glycogenesis) and renal injury (proteinuria and decreased creatinine clearance) were reported in rats exposed to 24 ppm bromoform for 2 months. A concentration of 4.8 ppm elicited no adverse effects after 2 months of exposure (Dykan, 1962).

3.2.3 Chronic Toxicity

3.2.3.1 Human

According to an abstract of a study by Dykan (1964), workers involved with bromoform production exhibited central nervous system and liver alterations. Further details were not provided.

3.2.3.2 Animal

Information on the chronic toxicity of bromoform in animals following inhalation exposure was not available.

3.2.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of bromoform in humans or animals following inhalation exposure was not available.

3.2.5 Reference Concentration

An inhalation reference concentration (RfC) has not been derived for bromoform.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

Information on the acute toxicity of bromoform in humans by other routes of exposure was not available.

3.3.1.2 Animal

The intraperitoneal LD50 for bromoform is 414 uL/kg (1196 mg/kg) in male rats (Agarwal and Mehendale, 1983), and the subcutaneous LD50 is 7.2 mmol/kg (1820 mg/kg) in male mice (Kutob and Plaa, 1962). Prolongation of pentobarbital sleeping time and liver lesions were reported in male mice administered a subcutaneous. injection of 4.4 mmol/kg bromoform (Kutob and Plaa, 1962). Agarwal and Mehendale (1983) tested the potentiation of chlordecone on bromoform toxicity and concluded that bromoform is not a potent hepatotoxin and that chlordecone does not potentiate its effects.

Undiluted bromoform was moderately irritating to rabbit eyes, but healing was complete in 1 to 2 days. Repeated skin contact caused moderate irritation to rabbit skin. Rabbits survived a single dose of 2000 mg/kg administered under a cuff of intact skin. Lethargy and slight weight loss were noted (Torkelson, 1994).

3.3.2 Subchronic Toxicity

Information on the subchronic toxicity of bromoform by other routes of exposure in humans or animals was not available.

3.3.3 Chronic Toxicity

Information on the chronic toxicity of bromoform by other routes of exposure in humans or animals was not available.

3.3.4 Developmental and Reproductive Toxicity

Information on the developmental or reproductive toxicity of bromoform by other routes of exposure in humans or animals was not available.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary target organs

  1. Liver. Subchronic and/or chronic oral exposure produced generally mild hepatic effects in rodents that included fatty liver changes, increased vacuolization, increased liver weights, and altered serum enzyme levels.
  2. Kidneys. Subchronic oral exposure produced histopathologic renal changes affecting the tubular epithelial cells and glomeruli and altered serum enzyme levels.

3.4.1.2 Other target organs

  1. Central nervous system. Subchronic and/or chronic oral exposure has caused lethargy in both sexes of rats, aggressiveness in male rats, and effects on operant behavior in mice.
  2. Development. Minor skeletal abnormalities were observed in fetuses of dams administered bromoform during gestation.
  3. Immune system. Subchronic oral exposure depressed humoral and cellular immunity in male mice.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

  1. Liver. Subchronic exposure produced impaired liver function in rats. Unspecified liver changes were reported in workers exposed to bromoform.
  2. Kidneys. Subchronic exposure produced impaired kidney function in rats.

3.4.2.2 Other target organs

  1. Central nervous system: Unspecified central nervous system effects were reported in workers exposed to bromoform.

3.4.3 Other Routes of Exposure

Target organs for other routes of exposure to bromoform were not identified.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Some epidemiologic studies suggest that there may be an association between exposure to trihalomethanes in drinking water and increased frequencies of cancers of the stomach, colon, rectum, or pancreas. However, these studies do not provide information whether the observed effects are due to bromoform or to one or more of the hundreds of other byproducts also present in chlorinated water (ATSDR, 1990). The evidence for carcinogenicity of bromoform in humans is considered inadequate (EPA, 1989).

4.1.2 Animal

Groups of F344/N rats and B6C3F1 mice were administered bromoform in corn oil by gavage, 5 days/week for 2 years, at doses of 0, 100, or 200 mg/kg (male and female rats and female mice) or at doses of 0, 50, or 100 mg/kg (male mice) (NTP, 1989). No evidence was observed of carcinogenic activity in mice. Neoplastic lesions (adenomatous polyps or adenocarcinomas) were observed in the colon or rectum of 3/50 male rats treated with 200 mg/kg and in 1/50 or 8/50 female rats treated with 100 or 200 mg/kg, respectively. Based on the occurrence of these uncommon neoplasms of the large intestine, the National Toxicology Program (NTP) (1989) concluded that there is some evidence of carcinogenic activity for male rats and clear evidence of carcinogenic activity for female rats. However, in a 24-month dietary study, Kurokawa (1987) observed no carcinogenic activity in male or female Wistar rats administered microencapsulated bromoform at concentrations of 400, 1600, or 6500 ppm (20, 80, or 325 mg/kg).

4.2 INHALATION EXPOSURES

Information on the carcinogenicity of bromoform in humans or animals following inhalation exposure was not available.

4.3 OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of bromoform in humans by other routes of exposure was not available.

4.3.2 Animal

In a lung tumor assay, Theiss et al. (1977) administered bromoform by intraperitoneal injection to male strain A mice at doses of 4, 48, or 100 mg/kg, 3 times weekly for a total of 24, 23, or 18 injections, respectively. Controls received the vehicle tricaprylin. Animals were sacrificed 24 weeks after the first injection. No effect on survival was observed in any of the treated groups. The number of lung tumors per mouse for the control, low-, mid-, and high-dose groups were 0.27, 0.53, 1.13, and 0.67, respectively (statistically significant only for the mid-dose group).

4.4 EPA WEIGHT-OF-EVIDENCE

Classification--B2, probable human carcinogen (EPA, 1995a)

Basis--Based on inadequate human data and sufficient evidence of carcinogenicity in animals (increased tumor incidence after oral and intraperitoneal administration in rats and mice, respectively). Bromoform is genotoxic in several assay systems and is structurally related to other trihalomethanes which have been verified as either probable or possible carcinogens.

4.5 CARCINOGENICITY SLOPE FACTORS

4.5.1 Oral

  • SLOPE FACTOR: 7.9E-3 (mg/kg/day)-1 (EPA, 1995a)
  • UNIT RISK: 2.3E-7 (ug/L)-1 (EPA, 1995a)
  • PRINCIPAL STUDY: NTP, 1989
  • COMMENT: The slope factor and unit risk are based on neoplastic lesions in the large intestines in female rats exposed to bromoform by gavage for 2 years.

4.5.2 Inhalation

  • SLOPE FACTOR: 3.9E-3 (mg/kg/day)-1 (EPA, 1995b)
  • UNIT RISK: 1.1E-6 (ug/m3)-1 (EPA, 1995a)
  • COMMENT: The inhalation slope factor and unit risk are based on route-to-route extrapolation from a 2-year gavage study with rats showing an increased incidence of neoplastic lesions in the large intestines. The tumorigenic response is considered a systemic rather than portal-of-entry effect. Pharmacokinetic data suggest that gastrointestinal absorption is rapid and biotransformation is an activating mechanism. A default value of 50% absorption was used because no data are available to quantify the extent of respiratory absorption.

5. REFERENCES

ACGIH (American Conference for Governmental Industrial Hygienists). 1991. Bromoform. In: Documentation of the Threshold Limit Values and Biological Exposure Indices, ACGIH, Cincinnati, OH, pp. 154-155.

Agarwal, A. K. and H. M. Mehendale. 1980. Absence of potentiation of bromoform hepatotoxicity and lethality by chlordecone. Toxicol. Lett. 15: 251-257.

Ahmed, A. E., V. L. Kubic and M. W. Anders. 1977. Metabolism of haloforms to carbon monoxide. I. In vitro studies. Drug Metab. Dispos. 5: 198-204.

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Bromoform and Chlorodibromomethane, Prepared by Life Systems, Inc., under Subcontract to Clement Associates, Inc., Contract No. 205-88-0608. ATSDR/TP-90-05.

Balster, R. L. and J. F. Borcelleca. 1982. Behavioral toxicity of trihalomethane contaminants of drinking water in mice. Environ. Health Perspect. 46: 127-136.

Bowman, F. J., J. F. Borcelleca and A. E. Munson. 1978. The toxicity of some halomethanes in mice. Toxicol. Appl. Pharmacol. 44: 213-215.

Budavari, S., M. J. O'Neil and A. Smith. 1989. The Merck Index, Merck & Co., Rahway, NJ, p. 215.

Chu, I., V. Secours, I. Marino and D. C. Villeneuve. 1980. The acute toxicity of four trihalomethanes in male and female rats. Toxicol. Appl. Pharmacol. 52: 351-353.

Chu, I., D. C. Villeneuve, V. E. Secours and G. C. Becking. 1982. Toxicity of trihalomethanes. II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health B17: 225-240.

Condie, L. W., C. L. Smallwood and R. D. Laurie. 1983. Comparative renal and hepatotoxicity of halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene chloride. Drug Chem. Toxicol. 6: 563-578.

Dykan, V. A. 1962. Changes in liver and kidney functions due to methylene bromide and bromoform. Nauchn. Tr. Ukr. Nauchn.-Issled. Inst. Gigieny Truda i Profzabolevanii 29: 82-90. (Chem. Abstr. 60:8541d)

Dykan, V. A. 1964. Problems on toxicology, clinical practice, and work hygiene in the production of bromine-organic compounds. Gigiena Sb: 100-103. (Chem. Abstr. 63: 15429g)

EPA (U.S. Environmental Protection Agency). 1989. Health and Environmental Effects Document for Bromoform, Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. ECAO-CIN-GO46.

EPA (U.S. Environmental Protection Agency). 1995a. Integrated Risk Information System (IRIS)., Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.

EPA (U.S. Environmental Protection Agency). 1995b. Health Effects Assessment Summary Tables, Annual FY-95, Prepared for the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC.

Graham, E. A. 1915. Late poisoning with chloroform and other alkyl halides in relationship to the halogen acids formed by their chemical association. J. Exp. Med. 221: 48-75. (Cited in EPA, 1995a).

Kurokawa, Y. 1987. Personal communication from Y. Kurokawa, National Institute of Hygienic Sciences, Tokyo, Japan, to R. Melnick, National Toxicology Program, NC. (Cited in EPA, 1995a)

Kutob, S. D. and G. L. Plaa. 1962. A procedure for estimating the hepatotoxic potential of certain industrial solvents. Toxicol. Appl. Pharmacol. 4: 354-361.

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