Guidelines for Canadian Drinking Water Quality: Guideline Technical Document - Haloacetic Acids

11.0 Classification and assessment

11.1 Monochloroacetic acid

There was no evidence of carcinogenicity of MCA in mice or rats in a lifetime study (NTP, 1992). Tests for mutagenicity and genotoxicity of MCA were also largely negative. Based on the lack of evidence for carcinogenicity, MCA has therefore been classified in Group IV.D in this assessment, unlikely to be carcinogenic to humans (Health Canada, 1994).

MCA has not been evaluated by the International Agency for Research on Cancer (IARC). The U.S. EPA (2003b) reported that, under the 1999 Draft Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999b), the data for MCA were considered "inadequate for an assessment of human carcinogenic potential."

Several long-term studies conducted with MCA failed to show carcinogenicity. The lowest NOAEL of all the studies was from the 104-week drinking water study with rats by DeAngelo et al. (1997), for which a NOAEL of 3.5 mg/kg bw per day was derived by Health Canada for treatment-related changes in body, liver, kidney and testes weights. This study was chosen for the risk assessment, based on the appropriateness of the vehicle used (drinking water), the absence of significant effects at the low dose, the length of the study as well as the form of MCA administered (i.e., neutralized solution).

The tolerable daily intake (TDI) for MCA is calculated as follows:

where:

• 3.5 mg/kg bw per day is the NOAEL in the DeAngelo et al. (1997) chronic rat study, as derived by Health Canada,
• 300 is the uncertainty factor (x10 for interspecies variation, x10 for intraspecies variation and x3 for database deficiencies, including lack of reproductive/developmental studies).

Using the TDI derived from the NOAEL, a health-based target can be calculated as follows:

where:

• 0.0117 mg/kg bw per day is the TDI, as derived above,
• 70 kg is the average body weight of an adult,
• 0.2 is the proportion of the daily intake allocated to drinking water; this is a default value, since there are insufficient data to calculate the actual value,
• 1.5 L is the average daily consumption of drinking water by an adult.

11.2 Dichloroacetic acid

Liver tumours in both mice and rats have been reported in several carcinogenicity bioassays (Herren-Freund et al., 1987; Bull et al., 1990; Daniel et al., 1992; Richmond et al., 1995; DeAngelo et al., 1996, 1999; Pereira and Phelps, 1996) and are considered sufficient evidence to classify DCA as an animal carcinogen. The exact mechanism for tumorigenicity has not been identified, and tests for mutagenicity and genotoxicity have been mostly negative or equivocal in bacterial and mammalian test systems. It is unknown at this time if the carcinogenicity of DCA is mediated by a non-genotoxic mechanism. DCA did not induce peroxisome proliferation (Tong et al., 1998b).

DCA has been classified in Group II, probably carcinogenic to humans, with sufficient evidence in animals and inadequate evidence in humans (Health Canada, 1994). IARC (2004) recently classified DCA as Group 2B, possibly carcinogenic to humans on the basis of sufficient evidence of its carcinogenicity in experimental animals and inadequate evidence of its carcinogenicity in humans. In the 2006 edition of the U.S. drinking water standards and health advisories, U.S. EPA (2006) considers DCA as "likely to be carcinogenic to humans" based on the 2005 U.S. EPA Guidelines for Carcinogen Risk Assessment. This is "based on current data and the lack of conclusive data regarding the mode of action of DCA at environmentally relevant doses" (U.S. EPA, 2003c). There is no information available on the mutagenic effects of DCA in humans (CHEMINFO, 2003c).

Liver tumours in both mice and rats have been reported in several carcinogenicity bioassays with DCA. Liver tumours (hepatocellular carcinomas) in mice were chosen for the cancer risk assessment, as the only rat study available used a high dose that was not well tolerated by the rats and had to be decreased several times. Therefore, cancer risks have been estimated on the basis of results of an adequate long-term drinking water study (90-100 weeks) in male B6C3F1 mice, which was conducted by DeAngelo et al. (1999). Liver tumours (hepatocellular carcinomas) seen in male mice showed an appropriate dose-response relationship. Other considerations for choosing the study for the risk assessment were the appropriateness of the vehicle used (drinking water), the form of DCA administered (i.e., neutralized solution), the length of the study as well as the use of numerous dose groups (five doses and a control group). A NOEL could not be determined for hepatocarcinogenicity because of the significant increase in hepatocellular carcinoma multiplicity observed at the lowest dose, 8 mg/kg bw per day (0.58 compared with 0.28 in the control) (DeAngelo et al., 1999).

Based on the classification of probable carcinogen and the uncertainty surrounding whether or not the carcinogenicity of DCA is mediated by a non-genotoxic mechanism, Health Canada has chosen to use a low-dose linear risk extrapolation for calculating the cancer risk. This is consistent with the most recent (2005) U.S. EPA Guidelines for Carcinogen Risk Assessment, which state that "when the weight of evidence evaluation of all available data are insufficient to establish the mode of action for a tumour site and when scientifically plausible based on the available data, linear extrapolation is used as a default approach, because linear extrapolation generally is considered to be a health-protective approach. Nonlinear approaches generally should not be used in cases where the mode of action has not been ascertained."

Therefore the unit risk can be assessed by the linearized multistage (LMS) method (Health Canada, 2004a), using the number of male B6C3F1 mice in each dose group having hepatocellular carcinomas following exposure to DCA in drinking water for 90-100 weeks (DeAngelo et al., 1999).

In this method, the multistage model is fit to the dose-response data, and the upper 95% confidence limit on the linear term is taken to be the unit risk. The multistage model is given by:

where d is dose, k is the number of dose groups in the study (excluding control), P(d) is the probability of the animal developing a tumour at dose d and q_i > 0, i = 0, ..., k are parameters to be estimated. The unit risk is defined as the increase in excess risk per unit dose, where excess risk is given by

The unit risk is applicable at very low doses, presumably in the range where humans would be exposed. For a small dose, d, the excess risk can be shown to be approximately equal to q₁d.

Thus, when the background P(0) is small, q₁ represents the slope (i.e., change in risk per increase of unit dose) of the dose-response curve in the low-dose region. In practice, the upper 95% confidence limit on q₁ is used and is denoted by q₁*. This is the unit risk for the LMS method.

The multistage model was fit using THRESH (Howe, 1995), and the unit risk was calculated by the LMS method without prior application of the kinetic adjustment factor. The P-value for the chi-square lack of fit test was 0.87, indicating that the model fit the data adequately. The units of the unit risks were converted to concentrations in drinking water by multiplying by the drinking rate of a human (1.5 L/day) and dividing by the standard body weight of a human (70 kg).

An animal-to-human kinetic adjustment factor (KA) (also known as allometric scaling factor, which corrrects for body weight differences between animals and humans) can also be applied. The animal-to-human kinetic adjustment factor (KA) is given by:

where 70 kg is the standard body weight of a human. Since the allometric scaling factor is applied to the unit risk after modelling, a mouse body weight of 43.9 g was used in the above formula. This was the average body weight in the control group.

The estimated calculated unit lifetime human cancer risk associated with the ingestion of DCA at 1 µg/L in drinking water is 1.02 × 10⁻⁶ (based on liver tumours, hepatocellular carcinomas).

In the context of drinking water guidelines, Health Canada has defined the term "essentially negligible" as a range from one new cancer above background per 100 000 people to one new cancer above background per 1 million people (i.e., 10⁻⁵ to 10⁻⁶) over a lifetime.

The estimated concentrations for these tumour types, based on the model described above, and the corresponding calculated unit lifetime human cancer risks are as follows:

Lifetime risk	Concentration in drinking water (µg/L)
10-4	98.1 (rounded to 100)
10-5	9.81 (rounded to 10)
10-6	0.98 (rounded to 1)

Using the most conservative concentration in drinking water estimated for a 10⁻⁵ lifetime human cancer risk, a health-based target of 0.01 mg/L (10 µg/L) is derived for DCA in drinking water.

An additional analysis was undertaken in which the kinetic adjustment factor was applied to the experimental doses before modelling the data. This was done in order to facilitate comparisons with the U.S. EPA's (2003c) methodology. The multistage model was fit using THRESH (Howe, 1995), and unit risks were calculated by LMS, with prior application of the kinetic adjustment factor. The results demonstrated that applying the animal-to-human kinetic adjustment factor before or after fitting the model had no impact on the resulting unit risks or concentrations.

11.3 Trichloroacetic acid

TCA administered in drinking water has consistently been shown to produce liver tumours in mice but not in rats. The mechanism underlying the mouse liver tumours was determined to be based on peroxisome proliferation, which may or may not be relevant to humans (Cattley et al., 1998). TCA was seen as weakly genotoxic.

Based on evidence of carcinogenicity being limited to one species of rodents, the mouse, and inadequate evidence in humans, TCA has been classified in Group III in this assessment, possibly carcinogenic to humans (Health Canada, 1994). According to IARC (1995), there is inadequate evidence for its carcinogenicity in humans and limited evidence for its carcinogenicity in experimental animals. U.S. EPA (1986) classified TCA as a possible human carcinogen, whereas U.S. EPA (2003b), under the 1999 Draft Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999b), stated that there is suggestive evidence for TCA carcinogenicity, but the data are not sufficient to assess human carcinogenicity.

Long-term drinking water studies produced liver tumours in mice, but not in rats. Since it is not known whether the underlying mechanism is relevant to humans, a long-term rat study with a non-cancer end-point was chosen for the risk assessment. The 104-week drinking water study by DeAngelo et al. (1997) also showed the lowest NOAEL of 32.5 mg/kg bw per day based on treatment-related changes (decreased body weight, increased liver serum enzyme activity and liver histopathology compared with control animals). Other considerations for choosing the study included the appropriateness of the vehicle used (drinking water), the absence of significant effects at the low dose, the length of the study and the form of TCA administered (i.e., neutralized solution).

The TDI for TCA can be calculated as follows:

where:

• 32.5 mg/kg bw per day is the NOAEL in the DeAngelo et al. (1997) chronic rat study,
• 1000 is the uncertainty factor (x10 for interspecies variation, x10 for intraspecies variation and x10 for database deficiencies, including lack of a multigenerational reproductive study, and possible carcinogenicity).

Using the TDI derived from the NOAEL, a health-based target can be calculated as follows:

where:

• 0.0325 mg/kg bw per day is the TDI, as derived above,
• 70 kg is the average body weight of an adult,
• 0.2 is the proportion of the daily intake allocated to drinking water; this is a default value, since there are insufficient data to calculate the actual value,
• 1.5 L/d is the average daily consumption of drinking water by an adult.

11.4 Monobromoacetic acid

There are insufficient data on the toxicity of MBA identified in this document to establish a health-based target. Acute oral studies have shown MBA to be acutely toxic. However, no subchronic, chronic or carcinogenic studies were conducted or published with MBA, nor was a standard developmental or multigeneration study conducted. Mixed results were seen with regards to mutagenicity/genotoxicity studies.

MBA has been classified in Group VI in this assessment, unclassifiable with respect to carcinogenicity in humans, based on inadequate data from animal studies (Health Canada, 1994).

U.S. EPA (2005a) reported that, under the 1999 Draft Revised Guidelines for Carcinogen Risk Assessment, the data for MBA were considered "inadequate for an assessment of human carcinogenic potential." MBA has not been evaluated or classified by IARC.

11.5 Dibromoacetic acid

Based on the only oral acute toxicity study, DBA has been shown to be moderately toxic. Available subchronic and chronic studies suggest that the liver is the target organ. Reproductive studies suggest male-mediated effects, whereas the reporting of developmental studies is limited to abstracts (limited data) but may suggest fetotoxicity. Additional studies need to be conducted in order to adequately assess the developmental toxicity of DBA. Available mutagenicity studies are limited and show mixed results.

In a recent 2-year drinking water study in mice and rats conducted by NTP (2007) (also published as a summary by Melnick et al., 2007), DBA was shown to be a multiple-organ carcinogen in laboratory animals, with tumour induction seen in the liver and lung of mice, in the abdominal cavity (mesotheliomas) of male rats and in the haematopoietic system (monocellular cell leukaemia) in female rats. As a result, Health Canada has classified DBA as Group II, probably carcinogenic to humans, based on sufficient evidence in animals and inadequate evidence in humans (Health Canada, 1994). DBA has not been evaluated or classified by IARC. In 2005, before the publication of these new studies, the U.S. EPA (2005a) had reported that, based on the 1999 Draft Revised Guidelines for Carcinogen Risk Assessment, the data for DBA were considered "inadequate for an assessment of human carcinogenic potential."

Based on DBA's new classification as a probable carcinogen, the linearized multistage method was chosen to calculate unit risks. The application of the multistage model is described in Section 11.2.

The multistage models were fit using THRESH (Howe, 1995) and the unit risks were calculated (Health Canada, 2007a). An animal-to-human kinetic adjustment factor (KA) was applied to the final unit risks assuming a rat weighs 0.35 kg, a mouse weighs 0.03 kg and a human weighs 70 kg. The KA formula is also described in Section 11.2. A chi-square lack of fit test was performed for the model fits. The degrees of freedom for this test are equal to k minus the number of q_i's whose estimates are non-zero. A p-value less than 0.05 indicates a significant lack of fit. Based on this criterion, a few models exhibited a significant lack of fit due to an uneven dose-response. Although no simple model will adequately describe these data, these models do provide a reasonable visual fit. This is in contrast to DCA, where the model fit the data adequately. The calculations for the unit risks (raw and converted using the allometic scaling factor) for DBA and lack of fit p-values are displayed in Health Canada (2007b).

The estimated unit lifetime risks associated with ingestion of 1 µg/L of DBA in drinking water were estimated to range from 0.14 × 10⁻⁶ to 4.26 × 10⁻⁶. The unit risk range was derived from mesotheliomas observed in male rats (0.14 × 10⁻⁶) as its lower bound (least sensitive) and hepatocellular adenoma/carcinoma in male mice (4.26 × 10⁻⁶) as its upper bound (most sensitive).

The estimated concentrations for these tumour types and the corresponding calculated unit lifetime human cancer risks are as follows:

Lifetime risk	Concentration in drinking water (µg/L)
10-4	23.5 - 701.6
10-5	2.3 - 70.2
10-6	0.23 - 7.0

Using the most conservative concentration in drinking water estimated for a 10⁻⁵ lifetime human cancer risk, a health-based target of 0.002 mg/L (2 µg/L) (rounded) is derived for DBA in drinking water.

11.6 International considerations

Several agencies have reviewed HAAs and have established guidelines or standards as a function of various factors, such as best available technology and/or health effects.

WHO (2004a, b, 2005) has established separate guideline values for three of the HAAs: MCA (20 µg/L), DCA (provisional guideline value of 50 µg/L) and TCA (200 µg/L). Although the World Health Organization (WHO) calculated a health-based guideline value of 40 µg/L for DCA based on a 10⁻⁵ upper-bound excess lifetime cancer risk, the guideline is provisional because "the data on treatment are insufficient to ensure that the 40 µg/litre value is technically achievable under a wide range of circumstances" (WHO, 2005). In regards to MBA and DBA, WHO (2004c) considered the databases inadequate for the derivation of guideline values.

The U.S. EPA (2006) has used a different approach and established a single maximum contaminant level (MCL) for all five HAAs (HAA5) of 0.06 mg/L based on best available technology, as well as individual non-enforceable maximum contaminant level goals of 0.03 mg/L for MCA, 0 for DCA (based on its carcinogenicity) and 0.02 mg/L for TCA.