State of the Science Report for Biphenyl

Exposure Assessment, Hazard Characterization and Risk Evaluation

Based on intakes of relevant media for six age groups of the general population and concentrations of biphenyl in ambient air (Hoff and Chan, 1987), indoor air (Otson et al., 1994), drinking water (Williams et al., 1982), dust (as a surrogate for soil) (Wilson et al., 2001) and a variety of food items (Braune et al., 1999; U.S. FDA, 2002a, 2003a), the upper-bounding estimate of intake for the most highly exposed age group (i.e., 0.5-4 years) is 1.5 µg/kg-bw per day for the general population (see Table 1). No data on concentrations of biphenyl in formula or breast milk were identified for Canada. However, given the absence of biphenyl in dairy products analysed by the U.S. FDA (2002a, 2003a), exposure of breast-fed infants is not expected to exceed that estimated for the other age groups. The estimates presented in Table 1 indicate that food is the largest source of exposure to biphenyl for most age groups in the general population, but this results in large measure from basing the estimated intakes from this medium on the limits of detection given in the critical studies. This likely results in an overestimate, the magnitude of which cannot be determined, and indoor and ambient air likely contribute proportionally more to exposure than indicated in the upper-bounding estimates. Measured values for air are consistent with what would be expected based on the available information on the environmental releases and chemical and physical properties of biphenyl. Cigarette smoke can also be a source of exposure to biphenyl, although data are currently insufficient to quantify the potential contribution to total intake.

Although there are limitations in the available database on exposure, confidence that actual exposures in Canada will not exceed the estimates presented here is high.

Based on a health assessment published by the International Programme on Chemical Safety (IPCS) in 1999, long-term exposure to biphenyl in the diet resulted in significant increases in the incidence of transitional cell papillomas and carcinomas of the urinary bladder in male rats and in a significant, although not dose-related, increase in the incidence of hepatocellular adenomas and carcinomas in female mice (Japan Bioassay Research Center, 1996; Umeda et al., 2002). In the rats, significant dose-related effects on serum enzyme levels (alkaline phosphatase, aspartate transaminase and alanine transaminase) and blood urea nitrogen levels were observed at 38 mg/kg-bw per day or greater, while hematological effects, calculi and histopathological changes in the bladder and/or kidney were noted at higher doses (Japan Bioassay Research Center, 1996). It has been suggested, as summarized in IPCS (1999), that bladder tumours observed in male rats exposed to some non-genotoxic chemicals may be correlated with regenerative hyperplasia caused by irritation as a result of calculi formed in the urinary bladder (Cohen, 1995). In this regard, IPCS (1999) noted that the mechanism of tumour formation has not been fully elucidated and that several outstanding issues exist that may suggest that such tumours are not solely the result of calculi formation in the urinary bladder; therefore, some concerns exist regarding the potential carcinogenicity of biphenyl to humans. In addition, although available data are not completely consistent, there is some indication in in vitro assays that biphenyl has some mutagenic potential (IPCS, 1999) (see Table 2). However, with few exceptions, valid results of quantitative structure-activity relationship and structure-activity relationship modelling, where biphenyl was not included in the training set, were negative.

In a series of early subchronic inhalation assays, non-neoplastic effects were observed in rats, including increased mortality and irritation of the mucous membranes, and in mice, including increased mortality and bronchopulmonary changes, at concentrations of 5-300 mg/m³ (Deichmann et al., 1947).

Confidence in the database on health effects is moderate to high, owing to an extensive data set, including various short-term, chronic, developmental and in vitro genotoxicity assays. However, the mode of action for carcinogenicity remains unclear.

Comparison of the lowest Lowest-Observed-Effect Level (LOEL) for non-neoplastic effects (i.e., alterations of serum enzyme and blood urea nitrogen levels) (38 mg/kg-bw per day) with the upper-bounding estimate of daily intake (1.5 µg/kg-bw per day) results in a margin of exposure (MOE) of approximately 25 000. However, since estimates of daily intake of biphenyl from food are largely based on detection limits, and as ambient and indoor air may be contributing proportionally more to daily intakes of biphenyl, margins of exposure for inhalation are also considered here. Therefore, an MOE of 5000 was also derived by comparing the lowest Lowest-Observed-Effect Concentration (LOEC) for non-neoplastic effects (mortality and respiratory irritation) (5 mg/m³) with the upper-bounding estimate of indoor air concentration (1 µg/m³). Although the margins for non-neoplastic effects are relatively large (5000-25 000), there are considerable uncertainties regarding the mode of induction of bladder and liver tumours in rodents and their relevance to humans

The outcome of this evaluation on 1,1-biphenyl is that it is suspected that these margins may not be adequate to account for the uncertainties in the mode of induction of tumours in experimental animals and intraspecies and interspecies variations in sensitivity . Data addressing these uncertainties would permit a more definitive conclusion.

Table 1: Upper-bounding estimates of daily intake of biphenyl by the general population of Canada

Route of exposure	Estimated intake ( µg/kg-bw per day) of biphenyl by various age groups
	0-6 months1, 2, 3		0.5-4 years4	5-11 years5	12-19 years6	20-59 years7	60+ years8
	formula fed	not formula fed
Ambient air9	7.7 × 10-4		1.7 × 10-3	1.3 × 10-3	7.3 × 10-4	6.3 × 10-4	5.5 × 10-4
Indoor air10	0.25		0.53	0.41	0.23	0.2	0.17
Drinking water 11	3.4 × 10-3	1.3 × 10-3	1.4 × 10-3	1.1 × 10-3	6.4 × 10-4	6.7 × 10-4	7.1 × 10-4
Food and beverages12		0.98	0.97	0.74	0.43	0.33	0.28
Soil13	3.2 × 10-5		5.2 × 10-5	1.7 × 10-5	4.0 × 10-6	3.4 × 10-6	3.3 × 10-6
Total intake	0.25	1.22	1.5	1.15	0.67	0.53	0.46

1. No data were identified on concentrations of biphenyl in breast milk.
   
   
2. Assumed to weigh 7.5 kg, to breathe 2.1 m³ of air per day, to drink 0.8 L of water per day (formula fed) or 0.3 L/day (not formula fed) and to ingest 30 mg of soil per day (EHD, 1998).
   
   
3. For exclusively formula-fed infants, intake from water is synonymous with intake from food. The concentration of biphenyl in water used to reconstitute formula was based on Williams et al. (1982). No data on concentrations of biphenyl in formula were identified for Canada. Approximately 50% of non-formula-fed infants are introduced to solid foods by 4 months of age and 90% by 6 months of age (NHW, 1990).
   
   
4. Assumed to weigh 15.5 kg, to breathe 9.3 m³ of air per day, to drink 0.7 L of water per day and to ingest 100 mg of soil per day (EHD, 1998).
   
   
5. Assumed to weigh 31.0 kg, to breathe 14.5 m³ of air per day, to drink 1.1 L of water per day and to ingest 65 mg of soil per day (EHD, 1998).
   
   
6. Assumed to weigh 59.4 kg, to breathe 15.8 m³ of air per day, to drink 1.2 L of water per day and to ingest 30 mg of soil per day (EHD, 1998).
   
   
7. Assumed to weigh 70.9 kg, to breathe 16.2 m³ of air per day, to drink 1.5 L of water per day and to ingest 30 mg of soil per day (EHD, 1998).
   
   
8. Assumed to weigh 72.0 kg, to breathe 14.3 m³ of air per day, to drink 1.6 L of water per day and to ingest 30 mg of soil per day (EHD, 1998).
   
   
9. The highest concentration of biphenyl measured in outdoor air along the Niagara River in Fort Erie, Niagara Falls and Niagara-on-the-Lake, Ontario, was 0.022 µg/m³ (Hoff and Chan, 1987). Canadians are assumed to spend 3 hours outdoors each day (EHD, 1998). This concentration is within the range of concentrations reported in another study of outdoor air in Canada (Patton et al., 1991) and many studies in the United States and Norway.
   
   
10. The concentration of biphenyl in indoor air, based on a composite of 757 indoor air sample extracts taken from Canadian residential homes, was 1 µg/m³ (Otson et al., 1994). Canadians are assumed to spend 21 hours indoors each day (EHD, 1998). This concentration is within the range of concentrations reported in studies of indoor air in Canada (Otson and Benoit, 1986), the United States (Wilson et al., 2001) and Finland (Kostiainen, 1995).
    
    
11. The highest concentration of biphenyl measured in 24 samples of drinking water from 12 Great Lakes municipalities in Ontario was 0.0319 µg/L (Williams et al., 1982). This was the highest value reported in the available studies carried out in Canada (Benoit et al., 1979a, 1979b; LeBel et al., 1987; City of Toronto Water and Wastewater Services Division, 2002a, 2002b, 2002c, 2002d).
    
    
12. Estimates of intake from food are based upon concentrations in foods that are selected to represent the 12 food groups addressed in calculating intake (EHD, 1998):
    
    Dairy products: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Fats: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Fruits and fruit products: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Vegetables: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Cereal products: 48 µg/kg; maximum concentration of five samples of oats, whole grain imported from Canada (U.S. FDA, 2003b)
    Meat and poultry: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Fish: 2.64 µg/kg; maximum concentration in 239 samples of freshwater fish from the Northwest Territories (Braune et al., 1999)
    Eggs: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Foods, primarily sugar: 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    Mixed dishes: no data identified
    Nuts and seeds: 7 µg/kg, highest concentration of biphenyl in 53 samples of cashews in the U.S. survey (U.S. FDA, 2002b)
    Beverages (soft drinks/alcohol/coffee/tea): 5 µg/kg; detection limit in U.S. survey (U.S. FDA, 2002a, 2003a)
    
    Amounts of foods consumed on a daily basis by each age group are described by Health Canada (EHD, 1998).
    
    
13. No data for biphenyl in soil in Canada were identified. The highest concentration of biphenyl found in dust samples collected at day care centres in Raleigh-Durham-Chapel Hill, North Carolina, was 8 µg/kg (Wilson et al., 2001). Although higher concentrations were reported in Norway (Vogt et al., 1987; Aamot et al., 1996), the data were not as recent, and U.S. data are considered more appropriate for estimating levels in Canadian soil.

Table 2: Summary of health effects information for biphenyl

Endpoint	Lowest effect levels1 /Results
Acute toxicity	Lowest oral LD50 > 1900 mg/kg-bw (BUA, 1990) Lowest inhalation LC50(rat) > 275 mg/m3 (Sun Co. Inc., 1977a) [Additional studies: Monsanto Co., 1959; Dow Chemical Co., 1974]
Short-term repeated-dose toxicity	Lowest oral (diet) LOEL (rat) = 50 mg/kg-bw per day: increased relative kidney weights, polycystic renal changes, increased urine volume and specific gravity (21-day study) (Sondergaard and Blom, 1979) [Additional studies: Booth et al., 1956, 1961] Lowest dermal LOEL (rabbit) = 500 mg/kg-bw per day: decreased body weight, histopathological effects (28-day study) (Deichmann et al., 1947) Lowest inhalation NOEC (mice) = 160 mg/m3 (no LOEL identified) (14-day study) (Sun Co. Inc., 1977b)
Subchronic toxicity	Lowest oral (diet) LOEL (rat) = 75 mg/kg-bw per day: polyuria, cloudiness of the urine, tubular dilation of the kidney (24-week study) (Booth et al., 1961) [Additional studies: Takita, 1983; Kurata et al., 1986; Shibata et al., 1989a, 1989b] Lowest inhalation LOEC (mice) = 5 mg/m3 (increased mortality and irritation of the respiratory tract) (4-week study) (based on limited study [Deichmann et al., 1947] involving no controls, small number of animals and exposure at one concentration only)
Chronic toxicity/ carcinogenicity	Lowest oral (diet) non-neoplastic LOEL (rat) = 38 mg/kg-bw per day: increased serum enzyme and blood urea nitrogen levels (2-year study) (Japan Bioassay Research Center, 1996; Umeda et al., 2002) [Additional studies: Newell, 1953; Takita, 1983; Shiraiwa et al., 1989] Dietary carcinogenicity bioassay in male and female rats : 0, 500, 1500 or 4500 mg/kg (0, 38, 113 or 338 mg/kg-bw per day; IPCS [1999] conversion) for 2 years; significant increases in the incidence of transitional cell papillomas and carcinomas of the urinary bladder in male rats at 338 mg/kg-bw per day (Japan Bioassay Research Center, 1996; Umeda et al., 2002) Dietary carcinogenicity bioassay in male and female mice : 0, 667, 2000 or 6000 mg/kg (0, 100, 300 or 900 mg/kg-bw per day; Health Canada [1994] conversion) for 104 weeks; female mice had significant increases in theincidenceof hepatocellular adenomas at 300 and 900 mg/kg-bw per day and in hepatocellular carcinomas at 300 mg/kg-bw per day (Japan Bioassay Research Center, 1996)
Developmental toxicity	Lowest oral (gavage) LOEL (rat) = 500 mg/kg-bw per day: fetal toxicity, including non-significant increases in fetuses with missing or non-ossified sternebrae; maternal toxicity at 1000 mg/kg-bw per day (gestation days 6-15) (Khera et al., 1979) [Additional studies: Stanford Research Institute, undated; Ambrose et al., 1960]
Reproductive toxicity	Lowest oral (diet) LOEL = 750 mg/kg-bw per day: decreased fertility, litter size and growth rate (Stanford Research Institute, undated)
Genotoxicity and related endpoints: in vivo	Chromosomal aberrations Negative: Rat, bone marrow (Kawachi et al., 1980) (no further information available) Negative: Rat, bone marrow (Dow Chemical Co., 1976) (inhalation, 64 or 320 mg/m3, 30 days) Comet assay Positive: Mice, stomach, liver, kidney, bladder, lung, brain, bone marrow (Sasaki et al., 1997) (oral, 200 mg/kg-bw)
Genotoxicity and related endpoints: in vitro	Chromosomal aberrations Positive: Chinese hamster cells, with activation (Sofuni et al., 1985) Negative: Chinese hamster cells, without activation (Abe and Sasaki, 1977; Ishidate and Odashima, 1977; Kawachi et al., 1980; Sofuni et al., 1985) DNA damage Positive: L5178Y cells (alkaline unwinding assay), with activation (Garberg et al., 1988) Negative: L5178Y cells (alkaline unwinding assay), without activation (Garberg et al., 1988) Human fibroblasts ("nick translation assay"), without activation (Snyder and Matheson, 1985) Bacillus subtilis (rec assay), without activation (Kawachi et al., 1980) Escherichia coli P637, with and without activation (Brams et al., 1987) Gene conversion Negative: Saccharomyces cerevisiae D3, with and without activation (Waters et al., 1982; Zimmermann et al., 1984) Mutagenicity Positive: L5178Y T/K+/- mouse lymphoma assay, with activation (Wangenheim and Bolcsfoldi, 1988) S. cerevisiae D7, with and without activation (Pagano et al., 1983) Chinese hamster cells (V79), with activation (Glatt et al., 1992) Negative: Salmonella typhimurium TA92, TA94, TA97, TA97a, TA98, TA100, TA102, TA1532, TA1535, TA1537, TA1538, TA2636, with and without activation (Cline and McMahon, 1977; Purchase et al., 1978; Kawachi et al., 1980; NTP, 1980; Bronzetti et al., 1981; Probst et al., 1981; Waters et al., 1982; Haworth et al., 1983; Pagano et al., 1983, 1988; Ishidate et al., 1984; Fujita et al., 1985; Brams et al., 1987; Bos et al., 1988; Glatt et al., 1992) E. coli , with and without activation (Cline and McMahon, 1977; Probst et al., 1981; Waters et al., 1982) S. cerevisiae D3, with and without activation (Waters et al., 1982; Zimmermann et al., 1984) Chinese hamster cells, without activation (Glatt et al., 1992) L5178Y T/K+/- mouse lymphoma assay, without activation (Wangenheim and Bolcsfoldi, 1988) Sister chromatid exchange Negative: Chinese hamster cells, without activation (Abe and Sasaki, 1977; Kawachi et al., 1980) Unscheduled DNA synthesis Negative: Rat, hepatocytes, with activation (Williams, 1978; Brouns et al., 1979; Probst et al., 1981) Human lung fibroblasts, with and without activation (Waters et al., 1982)

1. LC₅₀ = median lethal concentration; LD₅₀ = median lethal dose; LOEC = Lowest-Observed-Effect Concentration; LOEL = Lowest-Observed-Effect Level; NOEC = No-Observed-Effect Concentration; NOEL = No-Observed-Effect Level.