Page 5 - Fourth Report on Human Biomonitoring of Environmental Chemicals in Canada

11 Summary and results for nicotine metabolite

11.1 Cotinine

Cotinine (CASRN 486-56-6) is the major primary metabolite of nicotine, a chemical found naturally in the tobacco plant and present in tobacco products such as cigarettes, cigars, and smokeless tobacco products (e.g. chewing tobacco and snuff) (Benowitz and Jacob, 1994). Nicotine is also incorporated into nicotine replacement therapies such as the nicotine gum, patch, lozenge, inhaler, e-cigarettes, and buccal spray.

Human exposure to nicotine occurs primarily through the use of tobacco products, exposure to environmental tobacco smoke, and the use of nicotine replacement therapies (HSDB, 2009). In addition, infants breast fed by women who smoke may be exposed to nicotine in breast milk (HSDB, 2009).

Inhalation is the most effective intake route with on average 60% to 80% of nicotine absorbed through the lungs (Iwase et al., 1991). Nicotine can also be absorbed through the skin and gastrointestinal tract, but at a much lower efficiency (Karaconji, 2005). Once inside the body, approximately 70% to 80% of nicotine is metabolized into cotinine. It has a half-life of 10 to 20 hours and can remain in the body at detectable levels for up to 7 days (Benowitz and Jacob, 1994; Curvall et al., 1990; Hecht et al., 1999). Cotinine is considered to be the most relevant biomarker for exposure to tobacco products and tobacco smoke (Brown et al., 2005; CDC, 2009; Seaton and Vesell, 1993).

Tobacco smoke is a combination of gases, liquids, and breathable particles, some of which are harmful to human health. It contains over 4,000 chemicals, including at least 70 that cause, initiate, or promote cancer, and has been classified by the International Agency for Research on Cancer (IARC) as Group 1, carcinogenic to humans (Health Canada, 2011c; IARC, 2004). Exposure to these chemicals also contributes directly to other diseases, such as emphysema and heart disease, and an increased risk of asthma (CDC, 2004). During pregnancy, smoking may lead to miscarriages, low-birth-weight infants and less breast milk (WHO, 2010). Most of these chemicals are formed during the combustion of tobacco; others are found naturally in tobacco and are released as the tobacco burns (CDC, 2004). Smokeless tobaccos, including chewing tobacco and snuff, contain 28 known cancer-causing chemicals and, similar to the tobaccos used in cigarettes, pipes, and cigars, can lead to nicotine dependence and addiction (Health Canada, 2010g; IARC, 2007). Smokeless tobacco use causes oral, pancreatic, and esophageal cancer and has been classified by IARC as Group 1, carcinogenic to humans (IARC, 2007). It can also cause serious dental health problems, including recession of the gums, tooth loss, and discolouration of the teeth and gums (Walsh and Epstein, 2000). Levels of cotinine in the blood and urine of non-smokers have been correlated with some adverse health effects related to tobacco smoke exposure, and cotinine itself may contribute to the neuropharmacological effects of tobacco smoking (Benowitz, 1996; Crooks and Dwoskin, 1997).

As a result of the adverse health effects associated with tobacco use, the Government of Canada, along with provincial and territorial governments and various municipalities, has taken several steps to reduce the prevalence of tobacco use as well as exposure to tobacco smoke. These steps include prohibitions on the sale of tobacco to youth, requirements to apply health warnings on tobacco packaging, and restrictions on the promotion of tobacco products, including the display of tobacco products at retail outlets (Health Canada, 2006b). Additional steps include the offer of cessation help along with initiatives to eliminate smoking in workplaces and enclosed public locations (Health Canada, 2006b).

The First Nations Biomonitoring Initiative (FNBI) is a nationally representative biomonitoring study of adult First Nations peoples living on reserves south of the 60° parallel (AFN, 2013). It comprises 13 randomly selected First Nation communities in Canada with 503 First Nations participants aged 20 years and older. In 2011, the 50^th percentile concentrations of cotinine in urine from smokers and non-smokers were 315.79 µg/L and <1.1 µg/L, respectively. Data from cycle 1 (2007-2009) of the Canadian Health Measures Survey (CHMS) demonstrated that a substantial proportion of the Canadian population was exposed to secondhand smoke. The study found that certain non-smoking subpopulations, including children, adolescents, and those exposed to secondhand smoke in the home, had higher percentages with detectable cotinine concentrations (≥1.1 µg/L), indicating secondhand smoke exposure (Wong et al., 2013). A study of occupationally exposed non-smoking bar workers in the Toronto area examined the effects of a 2004 smoke-free workplace bylaw; the study showed a 1-month post-ban decline in the geometric mean of urinary cotinine from 10.3 µg/L to 3.10 µg/L (Repace et al., 2013). A concentration of 50 µg/L urine for cotinine is recommended for determining smoking status; levels greater than this concentration are attributed to smokers (SRNT Subcommittee on Biochemical Verification, 2002). Using this concentration, a study assessed the validity of self-reported cigarette smoking status among Canadians using urinary cotinine data from cycle 1 (2007-2009) of the CHMS (Wong et al., 2012). Compared with estimates based on urinary cotinine concentration, smoking prevalence based on self-reporting was only 0.3 percentage points lower, indicating that accurate estimates of the prevalence of cigarette smoking among Canadians can be derived from self-reported smoking status data.

Cotinine was analyzed in the urine of all CHMS participants aged 6-79 years in cycle 1 (2007-2009), and 3-79 years in cycle 2 (2009-2011), cycle 3 (2012-2013), and cycle 4 (2014-2015). Data from these cycles are presented as both µg/L and µg/g creatinine for non-smokers and smokers. Survey participants aged 3-11 years were assumed to be non-smokers. In this survey, a smoker is defined as someone who is a current daily or occasional smoker and a non-smoker is defined as someone who does not currently smoke and has either never smoked or who was previously a daily or occasional smoker. Finding a measurable amount of cotinine in urine is an indicator of exposure to nicotine.

In addition to free cotinine, nicotine and several other metabolites (cotinine-N-glucuronide, nicotine-N-glucuronide, trans-3-hydroxycotinine, trans-3-hydroxycotinine-O-glucuronide, and anabasine) were analyzed in cycle 1 (2007-2009) and cycle 3 (2012-2013) of the CHMS. Free and total 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of a tobacco-specific N-nitrosamine found only in tobacco and products derived from tobacco, were also analyzed in cycle 1 (2007-2009) and cycle 3 (2012-2013) of the CHMS. Data on these tobacco chemicals and their metabolites are available from Statistics Canada through the Research Data Centres Program.

Table 11.1.1 - Cotinine (non-smokers) - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 1 (2007-2009), cycle 2 (2009-2011), cycle 3 (2012-2013) and cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	5468	86.85	-	<LOD	<LOD	2.6^{Footnote E} (<LOD-4.4)	^{Footnote F}
3 (2012-2013)	4978	88.59	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	4907	88.95	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
Males, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	2594	84.93	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	2444	87.11	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
4 (2014-2015)	2446	86.84	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
Females, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	2874	88.59	-	<LOD	<LOD	1.5^{Footnote E} (<LOD-2.5)	^{Footnote F}
3 (2012-2013)	2534	90.02	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	2461	91.06	-	<LOD	<LOD	<LOD	^{Footnote F}
3-5 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	573	86.56	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	522	88.12	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
4 (2014-2015)	512	87.11	-	<LOD	<LOD	2.3 (1.7-3.0)	^{Footnote F}
6-11 years
1 (2007-2009)	1045	83.83	-	<LOD	<LOD	3.9^{Footnote E} (1.9-5.8)	10^{Footnote E} (5.7-14)
2 (2009-2011)	1061	83.79	-	<LOD	<LOD	4.9^{Footnote E} (1.9-7.9)	12^{Footnote E} (6.3-18)
3 (2012-2013)	1007	86.79	-	<LOD	<LOD	^{Footnote F}	7.1^{Footnote E} (2.7-11)
4 (2014-2015)	1008	89.88	-	<LOD	<LOD	<LOD	^{Footnote F}
12-19 years
1 (2007-2009)	882	80.27	-	<LOD	<LOD	8.3^{Footnote E} (3.8-13)	19^{Footnote E} (8.3-30)
2 (2009-2011)	928	80.06	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	889	82.56	-	<LOD	<LOD	^{Footnote F}	13^{Footnote E} (7.6-19)
4 (2014-2015)	901	84.79	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
20-39 years
1 (2007-2009)	874	85.35	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
2 (2009-2011)	1009	86.22	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	792	90.53	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	785	87.26	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
1 (2007-2009)	947	88.81	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
2 (2009-2011)	972	91.56	-	<LOD	<LOD	<LOD	^{Footnote F}
3 (2012-2013)	851	91.19	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	827	90.69	-	<LOD	<LOD	<LOD	^{Footnote F}
60-79 years
1 (2007-2009)	956	90.69	-	<LOD	<LOD	<LOD	^{Footnote F}
2 (2009-2011)	925	93.08	-	<LOD	<LOD	<LOD	^{Footnote F}
3 (2012-2013)	917	92.58	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	874	93.14	-	<LOD	<LOD	<LOD	^{Footnote F}
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^b Data not available as participants under the age of 6 years were not included in cycle 1 (2007-2009). ^E Use data with caution. ^F Data is too unreliable to be published.

Table 11.1.2 - Cotinine (non-smokers) (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 1 (2007-2009), cycle 2 (2009-2011), cycle 3 (2012-2013) and cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	5455	86.85	-	<LOD	<LOD	3.3 (<LOD-4.4)	^{Footnote F}
3 (2012-2013)	4976	88.59	-	<LOD	<LOD	<LOD	6.1^{Footnote E} (<LOD-10)
4 (2014-2015)	4906	88.95	-	<LOD	<LOD	2.6 (<LOD-3.5)	^{Footnote F}
Males, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	2588	84.93	-	<LOD	<LOD	3.9^{Footnote E} (<LOD-5.9)	^{Footnote F}
3 (2012-2013)	2444	87.11	-	<LOD	<LOD	2.4^{Footnote E} (<LOD-3.3)	^{Footnote F}
4 (2014-2015)	2445	86.84	-	<LOD	<LOD	2.6^{Footnote E} (<LOD-4.3)	^{Footnote F}
Females, 3-79 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	2867	88.59	-	<LOD	<LOD	3.0 (<LOD-3.9)	^{Footnote F}
3 (2012-2013)	2532	90.02	-	<LOD	<LOD	<LOD	5.2^{Footnote E} (<LOD-7.8)
4 (2014-2015)	2461	91.06	-	<LOD	<LOD	<LOD	^{Footnote F}
3-5 years
1 (2007-2009)^{Footnote b}	-	-	-	-	-	-	-
2 (2009-2011)	572	86.56	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	521	88.12	-	<LOD	<LOD	5.6^{Footnote E} (<LOD-7.7)	^{Footnote F}
4 (2014-2015)	512	87.11	-	<LOD	<LOD	3.7^{Footnote E} (2.2-5.2)	^{Footnote F}
6-11 years
1 (2007-2009)	1042	83.83	-	<LOD	<LOD	6.2^{Footnote E} (1.9-10)	^{Footnote F}
2 (2009-2011)	1059	83.79	-	<LOD	<LOD	5.2^{Footnote E} (1.9-8.5)	12^{Footnote E} (5.4-18)
3 (2012-2013)	1007	86.79	-	<LOD	<LOD	3.5^{Footnote E} (<LOD-5.8)	7.7^{Footnote E} (2.6-13)
4 (2014-2015)	1007	89.88	-	<LOD	<LOD	<LOD	^{Footnote F}
12-19 years
1 (2007-2009)	881	80.27	-	<LOD	<LOD	7.9^{Footnote E} (4.6-11)	^{Footnote F}
2 (2009-2011)	926	80.06	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	889	82.56	-	<LOD	<LOD	3.2^{Footnote E} (<LOD-5.5)	^{Footnote F}
4 (2014-2015)	901	84.79	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
20-39 years
1 (2007-2009)	871	85.35	-	<LOD	<LOD	4.5^{Footnote E} (<LOD-7.4)	^{Footnote F}
2 (2009-2011)	1007	86.22	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3 (2012-2013)	792	90.53	-	<LOD	<LOD	<LOD	3.3^{Footnote E} (<LOD-5.2)
4 (2014-2015)	785	87.26	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
1 (2007-2009)	944	88.81	-	<LOD	<LOD	4.6^{Footnote E} (<LOD-6.4)	^{Footnote F}
2 (2009-2011)	970	91.56	-	<LOD	<LOD	<LOD	4.7^{Footnote E} (<LOD-7.8)
3 (2012-2013)	850	91.19	-	<LOD	<LOD	<LOD	^{Footnote F}
4 (2014-2015)	827	90.69	-	<LOD	<LOD	<LOD	^{Footnote F}
60-79 years
1 (2007-2009)	956	90.69	-	<LOD	<LOD	<LOD	^{Footnote F}
2 (2009-2011)	921	93.08	-	<LOD	<LOD	<LOD	^{Footnote F}
3 (2012-2013)	917	92.58	-	<LOD	<LOD	<LOD	4.1^{Footnote E} (<LOD-6.8)
4 (2014-2015)	874	93.14	-	<LOD	<LOD	<LOD	^{Footnote F}
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^b Data not available as participants under the age of 6 years were not included in cycle 1 (2007-2009). ^E Use data with caution. ^F Data is too unreliable to be published.

Table 11.1.3 - Cotinine (smokers) - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 12-79 years by age group, Canadian Health Measures Survey cycle 1 (2007-2009), cycle 2 (2009-2011), cycle 3 (2012-2013) and cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 12-79 years
1 (2007-2009)	805	4.22	590 (420-820)	^{Footnote F}	1000 (810-1200)	2200 (2000-2400)	2600 (2300-2900)
2 (2009-2011)	819	5.74	490 (340-700)	^{Footnote F}	1000 (810-1200)	2200 (1900-2500)	2600 (2100-3100)
3 (2012-2013)	701	5.14	490 (410-590)	^{Footnote F}	990 (900-1100)	2000 (1600-2300)	2300 (2000-2600)
4 (2014-2015)	667	6.00	550 (420-710)	^{Footnote F}	1000 (830-1200)	2300 (1900-2700)	2800 (2400-3200)
Males, 12-79 years
1 (2007-2009)	406	4.43	660^{Footnote E} (400-1100)	^{Footnote F}	1200 (920-1500)	2300 (2000-2600)	2800 (2400-3300)
2 (2009-2011)	425	4.47	470^{Footnote E} (280-770)	^{Footnote F}	1000 (780-1200)	2300 (1900-2700)	2900 (2300-3500)
3 (2012-2013)	387	5.17	460 (340-630)	^{Footnote F}	990 (820-1100)	2100 (1700-2500)	2400 (2100-2600)
4 (2014-2015)	359	4.46	610 (470-800)	^{Footnote F}	980 (830-1100)	2200 (1800-2500)	2600 (1800-3400)
Females, 12-79 years
1 (2007-2009)	399	4.01	520 (390-700)	^{Footnote F}	860 (640-1100)	2100 (1900-2300)	2500 (2300-2700)
2 (2009-2011)	394	7.11	510^{Footnote E} (320-810)	^{Footnote F}	1000 (720-1300)	2100 (1800-2400)	2400 (1900-2900)
3 (2012-2013)	314	5.10	550 (380-790)	^{Footnote F}	990 (760-1200)	1700 (1200-2300)	2100 (1700-2500)
4 (2014-2015)	308	7.79	470^{Footnote E} (250-870)	^{Footnote F}	1100 (820-1400)	2500 (1900-3100)	2800 (2500-3100)
12-19 years
1 (2007-2009)	102	10.78	160^{Footnote E} (78-330)	<LOD	^{Footnote F}	1600 (1400-1900)	^{Footnote X}
2 (2009-2011)	102	11.76	^{Footnote F}	<LOD	^{Footnote F}	1700 (1200-2300)	^{Footnote X}
3 (2012-2013)	98	14.29	^{Footnote F}	^{Footnote X}	^{Footnote F}	^{Footnote X}	^{Footnote X}
4 (2014-2015)	73	19.18	^{Footnote F}	^{Footnote X}	430^{Footnote E} (260-610)	^{Footnote X}	^{Footnote X}
20-39 years
1 (2007-2009)	300	3.00	500^{Footnote E} (300-850)	^{Footnote F}	930 (620-1200)	2000 (1800-2200)	2500 (2100-2900)
2 (2009-2011)	311	9.00	400^{Footnote E} (260-630)	^{Footnote F}	850 (570-1100)	2200 (1600-2900)	2900 (2200-3600)
3 (2012-2013)	254	5.12	310^{Footnote E} (190-520)	^{Footnote F}	700^{Footnote E} (350-1100)	1600 (1300-1900)	2000 (1600-2400)
4 (2014-2015)	271	6.27	360^{Footnote E} (220-600)	^{Footnote F}	970 (620-1300)	2400 (1600-3200)	2900 (2200-3500)
40-59 years
1 (2007-2009)	275	3.27	830 (610-1100)	^{Footnote F}	1200 (910-1500)	2500 (2200-2800)	2800 (2400-3100)
2 (2009-2011)	253	1.58	800^{Footnote E} (480-1300)	^{Footnote F}	1400 (1000-1700)	2200 (1900-2600)	2600 (2000-3300)
3 (2012-2013)	228	2.63	770 (550-1100)	340^{Footnote E} (150-530)	1000 (890-1200)	2100 (1700-2600)	2300 (2000-2700)
4 (2014-2015)	208	2.88	880 (770-1000)	360^{Footnote E} (190-540)	1100 (870-1400)	2600 (1900-3200)	2900 (2400-3300)
60-79 years
1 (2007-2009)	128	3.91	650^{Footnote E} (430-980)	^{Footnote F}	860 (600-1100)	2200 (1900-2400)	^{Footnote X}
2 (2009-2011)	153	1.96	^{Footnote F}	^{Footnote F}	980 (720-1200)	1800 (1500-2000)	^{Footnote X}
3 (2012-2013)	121	2.48	940 (800-1100)	390^{Footnote E} (240-540)	990 (830-1200)	2100 (1400-2700)	^{Footnote X}
4 (2014-2015)	115	2.61	920 (720-1200)	440^{Footnote E} (250-630)	990^{Footnote E} (620-1400)	1900 (1500-2200)	^{Footnote X}
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published. ^X Suppressed to meet the confidentiality requirements of the Statistics Act.

Table 11.1.4 - Cotinine (smokers) (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 12-79 years by age group, Canadian Health Measures Survey cycle 1 (2007-2009), cycle 2 (2009-2011), cycle 3 (2012-2013) and cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 12-79 years
1 (2007-2009)	803	4.22	650 (480-890)	^{Footnote F}	1000 (830-1200)	3000 (2500-3500)	4400 (3500-5300)
2 (2009-2011)	816	5.74	430^{Footnote E} (290-630)	^{Footnote F}	840 (620-1100)	2700 (1800-3700)	3800^{Footnote E} (2300-5300)
3 (2012-2013)	701	5.14	440 (340-570)	^{Footnote F}	750 (590-900)	2600^{Footnote E} (1600-3700)	3900^{Footnote E} (2100-5800)
4 (2014-2015)	666	6.00	480 (360-630)	^{Footnote F}	780 (650-910)	2500 (1700-3300)	3300 (2900-3700)
Males, 12-79 years
1 (2007-2009)	405	4.43	560^{Footnote E} (360-880)	^{Footnote F}	930 (680-1200)	2300 (1900-2700)	3200 (2300-4200)
2 (2009-2011)	425	4.47	370^{Footnote E} (210-620)	^{Footnote F}	730 (480-980)	2700^{Footnote E} (1600-3700)	3700^{Footnote E} (2300-5100)
3 (2012-2013)	387	5.17	360^{Footnote E} (250-520)	^{Footnote F}	710 (500-920)	2300 (1500-3100)	3000^{Footnote E} (1900-4100)
4 (2014-2015)	358	4.46	500 (410-610)	^{Footnote F}	770 (630-900)	2900^{Footnote E} (1600-4200)	3300 (2500-4200)
Females, 12-79 years
1 (2007-2009)	398	4.01	780 (590-1000)	^{Footnote F}	1100 (900-1400)	3700 (2900-4500)	5500 (4300-6600)
2 (2009-2011)	391	7.11	520^{Footnote E} (300-890)	^{Footnote F}	1000 (650-1400)	^{Footnote F}	4800^{Footnote E} (2300-7400)
3 (2012-2013)	314	5.10	600 (420-850)	^{Footnote F}	860^{Footnote E} (510-1200)	3200^{Footnote E} (1000-5300)	4900 (3300-6400)
4 (2014-2015)	308	7.79	450^{Footnote E} (240-850)	^{Footnote F}	830^{Footnote E} (440-1200)	2500 (1800-3100)	^{Footnote F}
12-19 years
1 (2007-2009)	102	10.78	120^{Footnote E} (58-250)	<LOD	290^{Footnote E} (<LOD-470)	1400^{Footnote E} (600-2200)	^{Footnote X}
2 (2009-2011)	102	11.76	^{Footnote F}	<LOD	^{Footnote F}	1300 (990-1500)	^{Footnote X}
3 (2012-2013)	98	14.29	^{Footnote F}	^{Footnote X}	^{Footnote F}	^{Footnote X}	^{Footnote X}
4 (2014-2015)	72	19.18	^{Footnote F}	^{Footnote X}	^{Footnote F}	^{Footnote X}	^{Footnote X}
20-39 years
1 (2007-2009)	299	3.00	510^{Footnote E} (310-840)	^{Footnote F}	850 (560-1100)	2200 (1900-2600)	2500 (1900-3000)
2 (2009-2011)	311	9.00	330^{Footnote E} (200-530)	^{Footnote F}	710 (470-940)	2300 (1500-3000)	3200^{Footnote E} (1700-4700)
3 (2012-2013)	254	5.12	230^{Footnote E} (120-410)	^{Footnote F}	520^{Footnote E} (310-720)	1500^{Footnote E} (830-2200)	2100^{Footnote E} (1300-2900)
4 (2014-2015)	271	6.27	300^{Footnote E} (170-520)	^{Footnote F}	600 (390-800)	2300^{Footnote E} (1200-3400)	3200 (2300-4200)
40-59 years
1 (2007-2009)	275	3.27	1000 (810-1300)	^{Footnote F}	1300 (920-1600)	4100 (2900-5400)	5500 (4400-6600)
2 (2009-2011)	251	1.58	710^{Footnote E} (400-1200)	^{Footnote F}	990^{Footnote E} (560-1400)	3400^{Footnote E} (1400-5400)	4900^{Footnote E} (2800-7000)
3 (2012-2013)	228	2.63	840^{Footnote E} (520-1300)	390^{Footnote E} (190-580)	940^{Footnote E} (570-1300)	3500^{Footnote E} (1500-5500)	5200^{Footnote E} (2500-7800)
4 (2014-2015)	208	2.88	780 (610-1000)	210^{Footnote E} (120-300)	1000 (740-1300)	3000 (2200-3700)	3300 (2700-4000)
60-79 years
1 (2007-2009)	127	3.91	840^{Footnote E} (530-1300)	^{Footnote F}	1300 (1000-1500)	3200 (2100-4300)	^{Footnote X}
2 (2009-2011)	152	1.96	^{Footnote F}	^{Footnote F}	1000 (700-1400)	3000^{Footnote E} (1700-4300)	^{Footnote X}
3 (2012-2013)	121	2.48	960 (730-1200)	390 (270-500)	960^{Footnote E} (530-1400)	3100^{Footnote E} (1600-4700)	^{Footnote X}
4 (2014-2015)	115	2.61	980 (780-1200)	400^{Footnote E} (250-560)	1100 (820-1400)	2100 (1700-2500)	^{Footnote X}
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^X Suppressed to meet the confidentiality requirements of the Statistics Act. ^F Data is too unreliable to be published.

12 Summaries and results for organophosphate pesticide metabolites

12.1 Chlorpyrifos metabolite

The chemical 3,5,6-trichloro-2-pyridinol (TCPy; CASRN 6515-38-4) is a metabolite of chlorpyrifos and chlorpyrifos-methyl, both organophosphate insecticides, and triclopyr, a carboxylic acid herbicide. Chlorpyrifos was first introduced in 1965 to control pests associated with turfgrass, ornamentals, and indoor environments (CCME, 2008). It is also used in agricultural applications to control insects on food crops such as grains, fruit, nuts, and vegetables. The use of chlorpyrifos in Canada has changed drastically since the late 1990s owing to the discontinued use of most residential/homeowner applications and commercial applications in and around residential areas (CCME, 2008). Chlorpyrifos is currently used in agricultural, non-agricultural (e.g. structural), forestry and residential settings, as well as for mosquito control (Health Canada, 2007b). There are over 25 chlorpyrifos-containing acaricide and insecticide products registered in Canada (Health Canada, 2016d). Chlorpyrifos-methyl has not been registered for use in Canada, but is used agriculturally in other countries around the world (CDC, 2009; Health Canada, 2016d). Triclopyr is a selective herbicide used to kill unwanted broadleaf plants in agricultural (non-food areas) and forest environments. There are 19 products currently registered in Canada that contain the triclopyr ester and amine salt formulations (Health Canada, 2016d). However, in humans, triclopyr is excreted almost completely unchanged in the urine, indicating that TCPy is not a useful biomarker of exposure to triclopyr (Carmichael et al., 1989). Therefore, this summary will focus only on TCPy as a biomarker of exposure to chlorpyrifos and chlorpyrifos-methyl.

Chlorpyrifos binds tightly to soil particles and is not expected to leach significantly (ATSDR, 1997). Dispersion generally occurs via volatilization from moist soils or surface waters. Chlorpyrifos is moderately persistent in terrestrial and aquatic environments, with a half-life ranging from less than 1 week to more than 24 weeks (Eisler, 2000; Jarvinen and Tanner, 1982). In water and soil, TCPy is one of the major transformation products of chlorpyrifos (CCME, 2008).

The primary routes of exposure are oral, dermal, and inhalation through ingestion of food and drinking water, handling chlorpyrifos-containing pesticide products, and environmental exposure in insecticide-treated areas (ATSDR, 1997). Following entry into the body, chlorpyrifos is rapidly absorbed, metabolized, and excreted, predominantly in urine and to a lesser degree in feces (FAO/WHO, 2000). Accumulation in tissues is low owing to an elimination half-life of 27 hours (Nolan et al., 1984). Chlorpyrifos is rapidly metabolized by oxidative desulfuration and hydrolysis to form TCPy and dialkyl phosphate metabolites (diethylphosphate and diethylthiophosphate) (ATSDR, 1997). Diethylphosphate and diethylthiophosphate are semi-specific organophosphate pesticide metabolites associated with several pesticides (e.g. coumaphos, diazon, phorate, phosalone, terbufos) in addition to chlorpyrifos. TCPy is a more specific metabolite and is the major chlorpyrifos metabolic product. TCPy can be found in blood and urine (ATSDR, 1997). Urine is the principal route of excretion for TCPy and levels in urine are correlated with the degree of recent (within 48 hours) exposure to chlorpyrifos (ATSDR, 1997). The presence of TCPy in urine may also be the result of exposure to chlorpyrifos-methyl. In the environment, TCPy can also be found as a result of the breakdown of parent compounds. As TCPy is more persistent than its parent compounds in the environment, urinary levels may reflect direct environmental exposure to the metabolite (EPA, 2006b). TCPy and the dialkly phosphate metabolites are considered to be less toxic than their parents, chlorpyrifos and chlorpyrifos-methyl.

Chlorpyrifos and chlorpyrifos-methyl, as with other organophosphates pesticides, are cholinesterase inhibitors that act on the nervous system of insects and mammals by interfering with the transmission of nerve impulses (EPA, 1999). Failure to properly metabolize acetylcholine results in an overstimulation of the nervous system. Symptoms of acute overexposure may include headache, dizziness, fatigue, irritation of the eyes or nose, nausea, vomiting, salivation, sweating, and changes in heart rate. Organophosphate-induced delayed polyneuropathy has also been observed in humans following acute-duration exposure to chlorpyrifos (ATSDR, 1997). Very high exposures can have effects such as paralysis, seizures, loss of consciousness, or even death (ATSDR, 1997). However, typical exposure through the ingestion of chlorpyrifos in food is estimated to be low (ATSDR, 1997). Further, there is a growing body of evidence of adverse neurodevelopmental outcomes in infants and children following low-dose gestational and/or early postnatal exposure to chlorpyrifos (EPA, 2016). Chlorpyrifos is not considered to be mutagenic or carcinogenic (EPA, 2006; Health Canada, 1986c; NTP, 1992).

The sale, use, and maximum food residue limits (MRLs) of chlorpyrifos are regulated in Canada by Health Canada's Pest Management Regulatory Agency (PMRA) under the Pest Control Products Act (Canada, 2006). PMRA evaluates the toxicity of pesticides and potential exposure to determine whether a pesticide should be registered for a specific use. As part of the registration process, PMRA establishes MRLs of pesticides in food, including chlorpyrifos (Health Canada, 2016g). In 1999, PMRA commenced a re-evaluation of the 27 organophosphate pesticides, including chlorpyrifos, that were registered for use at that time in Canada (Health Canada, 1999a). The re-evaluation of chlorpyrifos has been carried out in three phases. The first phase comprised a phase-out of most residential uses, discontinued use on tomatoes, and lowered MRLs for residues in imported apples and grapes (Health Canada, 2000). The second phase focused on the remaining agricultural and forestry uses of chlorpyrifos (Health Canada, 2007b). The third phase will identify and implement, where warranted, measures to reduce environmental exposures (Health Canada, 2007b).

Health Canada, in collaboration with the Federal-Provincial-Territorial Committee on Drinking Water, has developed a guideline for Canadian drinking water quality that establishes the maximum acceptable concentration for chlorpyrifos in drinking water using an acceptable daily intake for chlorpyrifos derived by the Food and Agriculture Organization of the United Nations and the World Health Organization (FAO/WHO, 1982; Health Canada, 1986c). Chlorpyrifos has also been analyzed as part of Health Canada's ongoing Total Diet Study surveys (Health Canada, 2013d). The food items analyzed represent those that are most typical of the Canadian diet, and the surveys are used to provide dietary exposure estimates for chemicals that Canadians in different age-sex groups are exposed to through the food supply.

TCPy was analyzed in the urine of Canadian Health Measures Survey participants aged 3-79 years in cycle 4 (2014-2015). Data are presented as µg/L and µg/g creatinine. TCPy was also measured in cycle 3 (2012-2013); however, the data are not yet available because of ongoing quality assurance confirmation of the biospecimen analysis. Finding a measurable amount of TCPy in urine is an indicator of exposure to chlorpyrifos or chlorpyrifos-methyl and does not necessarily mean that an adverse health effect will occur.

Table 12.1.1 - 3,5,6-Trichloro-2-pyridinol - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2422	1.28	1.4 (1.2-1.5)	0.37 (0.30-0.44)	1.3 (1.1-1.4)	5.7 (4.4-7.0)	9.3 (6.5-12)
Males, 3-79 years
4 (2014-2015)	1209	1.41	1.5 (1.3-1.8)	0.47 (0.31-0.63)	1.4 (1.3-1.6)	6.4^{Footnote E} (4.0-8.8)	9.9^{Footnote E} (5.0-15)
Females, 3-79 years
4 (2014-2015)	1213	1.15	1.2 (1.0-1.4)	0.31 (0.23-0.40)	1.1 (0.94-1.3)	5.2 (3.7-6.7)	7.8 (5.3-10)
3-5 years
4 (2014-2015)	479	1.67	1.3 (1.1-1.5)	0.39 (0.28-0.49)	1.1 (0.81-1.4)	4.4 (3.4-5.4)	7.3^{Footnote E} (4.5-10)
6-11 years
4 (2014-2015)	489	0.41	1.6 (1.3-2.1)	0.45 (0.36-0.53)	1.4 (1.0-1.8)	6.3 (4.3-8.4)	^{Footnote F}
12-19 years
4 (2014-2015)	478	0	1.5 (1.3-1.7)	0.35^{Footnote E} (0.19-0.50)	1.2 (0.99-1.5)	7.0 (4.4-9.6)	11^{Footnote E} (6.3-15)
20-39 years
4 (2014-2015)	336	1.49	1.3 (1.1-1.5)	0.36 (0.26-0.45)	1.2 (1.0-1.5)	6.0 (4.4-7.6)	8.4 (5.9-11)
40-59 years
4 (2014-2015)	299	3.01	1.3 (1.1-1.7)	0.39^{Footnote E} (0.19-0.59)	1.3 (1.0-1.6)	5.0^{Footnote E} (2.5-7.5)	^{Footnote F}
60-79 years
4 (2014-2015)	341	2.05	1.4 (1.2-1.7)	0.35 (0.22-0.48)	1.2 (1.0-1.5)	6.0^{Footnote E} (3.5-8.5)	9.7^{Footnote E} (3.8-16)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 12.1.2 - 3,5,6-Trichloro-2-pyridinol (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2421	1.28	1.2 (1.1-1.4)	0.40 (0.32-0.49)	1.0 (0.92-1.1)	4.1 (3.4-4.8)	8.0^{Footnote E} (4.9-11)
Males, 3-79 years
4 (2014-2015)	1208	1.41	1.2 (1.0-1.4)	0.38 (0.26-0.50)	1.0 (0.91-1.1)	4.3 (3.3-5.3)	9.4^{Footnote E} (4.3-15)
Females, 3-79 years
4 (2014-2015)	1213	1.15	1.2 (1.1-1.5)	0.42 (0.34-0.50)	1.0 (0.84-1.2)	3.8 (2.7-4.9)	6.9^{Footnote E} (3.5-10)
3-5 years
4 (2014-2015)	479	1.67	2.2 (1.9-2.5)	0.87 (0.72-1.0)	1.9 (1.4-2.3)	6.8 (5.4-8.2)	10 (6.8-13)
6-11 years
4 (2014-2015)	488	0.41	1.8 (1.4-2.2)	0.58 (0.46-0.70)	1.5 (1.0-1.9)	5.5^{Footnote E} (3.2-7.7)	^{Footnote F}
12-19 years
4 (2014-2015)	478	0	1.0 (0.93-1.2)	0.34 (0.27-0.42)	0.96 (0.84-1.1)	4.3 (2.8-5.8)	6.6^{Footnote E} (3.2-9.9)
20-39 years
4 (2014-2015)	336	1.49	1.1 (0.87-1.3)	0.37 (0.26-0.48)	0.99 (0.73-1.3)	3.3 (2.4-4.2)	4.4 (3.3-5.6)
40-59 years
4 (2014-2015)	299	3.01	1.2 (0.92-1.5)	0.41^{Footnote E} (0.26-0.57)	0.96 (0.79-1.1)	^{Footnote F}	9.7^{Footnote E} (<LOD-16)
60-79 years
4 (2014-2015)	341	2.05	1.4 (1.2-1.6)	0.44 (0.33-0.54)	1.2 (0.96-1.4)	4.5 (3.2-5.8)	7.4^{Footnote E} (3.7-11)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

12.2 Malathion metabolite

Malathion dicarboxylic acid (CASRN 1190-28-9) is a metabolite of malathion, which is a broad-spectrum organophosphate insecticide that has been registered for use in Canada since 1953 (Health Canada, 2003a). Malathion is registered for the control of crawling and flying insects in agricultural, non-agricultural (e.g. structural), and residential settings, as well as for mosquito abatement (Health Canada, 2012e). Malathion is found in 27 acaricide and insecticide products registered in Canada (Health Canada, 2016d).

Malathion binds moderately to soil particles and undergoes significant biodegradation and hydrolysis such that it is generally not expected to leach into groundwater (ATSDR, 2003b). Dispersion from moist soils or surface waters generally occurs via volatilization. In air, malathion can be oxidized resulting in the formation of its active metabolite, malaoxon. Malathion is moderately persistent in terrestrial and aquatic environments, staying in the environment from a few days to several months (ATSDR, 2003b).

The primary routes of exposure are oral, dermal, and inhalation, and may occur through ingestion of food and drinking water, handling malathion-containing pesticide products and environmental exposure in insecticide-treated areas (ATSDR, 2003b). Following ingestion, malathion is rapidly absorbed from the gastrointestinal tract and metabolized in the liver; the metabolites are excreted, predominantly in urine (ATSDR, 2003b). Accumulation in tissues is low owing to an elimination half-life of less than 24 hour s (Bouchard et al., 2003; Vasilic et al., 1999). Malathion is rapidly metabolized by oxidation, hydrolysis, and the elimination of a methyl group catalyzed by glutathione S- transferase (ATSDR, 2003b). Malathion metabolism results in the formation of malaoxon, malathion monocarboxylic acid, malathion dicarboxylic acid, dialkyl phosphate metabolites, and other metabolites. Dialkyl phosphate metabolites are semi-specific organophosphate pesticide metabolites associated with several pesticides (e.g. azinophos-methyl, dimethoate, phosmet) in addition to malathion. Malathion dicarboxylic acid is a major urinary metabolite of malathion (ATSDR, 2003b). Malathion dicarboxylic acid can also be found in the environment as a result of the breakdown of the parent compound. Both dialkyl phosphate metabolites and malathion dicarboxylic acid are considered to be less toxic than their parent, malathion.

Malathion, as with other organophosphates pesticides, is a cholinesterase inhibitor that acts on the nervous system of insects and mammals by interfering with the transmission of nerve impulses (EPA, 1999). The majority of the systemic effects observed following exposure to malathion are due to the action of its active metabolite, malaoxon, on the nervous system (ATSDR, 2003b). Inhibition of acetylcholine metabolism results in an overstimulation of the nervous system. Symptoms of acute overexposure may include headache, dizziness, fatigue, irritation of the eyes or nose, nausea, vomiting, salivation, sweating, and changes in heart rate. Very high exposures can have effects such as difficulty breathing, dizziness, loss of consciousness, or even death (ATSDR, 2003b). However, compared with other organophosphate pesticides, malathion has low acute toxicity and Health Canada's Pest Management Regulatory Agency (PMRA) has concluded that risk to health from dietary exposure is not of concern (CDC, 2009; Health Canada, 2012e). Human health effects from malathion at low environmental levels are unknown, although some animal studies have suggested that there is a potential for toxic effects resulting from chronic low-dose exposure to organophosphates (Ray and Richards, 2001). Health Canada determined that malathion was unlikely to pose a carcinogenic risk to humans, nor was it found to be genotoxic or teratogenic in animal studies (Health Canada, 2010h). More recently, malathion was classified as Group 2A, probably carcinogenic to humans, by the International Agency for Research on Cancer on the basis of evidence in experimental animals (IARC, 2017).

The sale, use, and maximum food residue limits (MRLs) of malathion are regulated in Canada by Health Canada's PMRA under the Pest Control Products Act (Canada, 2006). PMRA evaluates the toxicity of pesticides and potential exposure in order to determine whether a pesticide should be registered for a specific use. As part of the registration process, PMRA establishes MRLs of pesticides in food, including malathion (Health Canada, 2016g). In 1999, PMRA commenced a re-evaluation of the 27 organophosphate pesticides, including malathion, that were registered for use at that time in Canada (Health Canada, 1999a). The re-evaluation of malathion was carried out in two phases. The first phase comprised an assessment of malathion use as an adulticide in mosquito abatement programs and resulted in mitigation measures including label changes for related end-use products (Health Canada, 2003b). The second phase included all registered uses and the metabolite malaoxon in the re-evaluation of malathion (Health Canada, 2012e). The re-evaluation found that most uses of malathion, including commercial products applied in agricultural, non-agricultural, and residential settings, do not pose unacceptable risks to human health.

Health Canada, in collaboration with the Federal-Provincial-Territorial Committee on Drinking Water, has developed a guideline for Canadian drinking water quality that establishes the maximum acceptable concentration for malathion using an acceptable daily intake derived by the Food and Agriculture Organization of the United Nations and the World Health Organization (FAO/WHO, 1973; Health Canada, 1986d). Malathion is also included in the list of various chemicals analyzed as part of Health Canada's ongoing Total Diet Study surveys (Health Canada, 2013d). The food items analyzed represent those that are most typical of the Canadian diet, and the surveys are used to provide dietary exposure estimates for chemicals that Canadians in different age-sex groups are exposed to through the food supply.

Malathion dicarboxylic acid was analyzed in the urine of all Canadian Health Measures Survey participants aged 3-79 years in cycle 4 (2014-2015). Data are presented as both μg/L and μg/g creatinine. Malathion dicarboxylic acid was also measured in cycle 3 (2012-2013); however, the data are not yet available because of ongoing quality assurance confirmation of the biospecimen analysis. Finding a measurable amount of malathion dicarboxylic acid in urine is an indicator of exposure to malathion and does not necessarily mean that an adverse health effect will occur.

Table 12.2.1 - Malathion dicarboxylic acid - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2519	82.93	-	<LOD	<LOD	0.46^{Footnote E} (0.23-0.69)	0.95^{Footnote E} (0.46-1.4)
Males, 3-79 years
4 (2014-2015)	1257	83.13	-	<LOD	<LOD	0.31^{Footnote E} (<LOD-0.47)	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1262	82.73	-	<LOD	<LOD	0.68^{Footnote E} (0.25-1.1)	1.3^{Footnote E} (0.58-2.0)
3-5 years
4 (2014-2015)	499	80.76	-	<LOD	<LOD	0.70 (0.44-0.95)	1.8^{Footnote E} (0.62-3.0)
6-11 years
4 (2014-2015)	510	79.41	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
12-19 years
4 (2014-2015)	501	82.83	-	<LOD	<LOD	0.31^{Footnote E} (<LOD-0.53)	0.89 (0.62-1.2)
20-39 years
4 (2014-2015)	357	89.08	-	<LOD	<LOD	^{Footnote F}	0.78^{Footnote E} (0.23-1.3)
40-59 years
4 (2014-2015)	302	83.77	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
60-79 years
4 (2014-2015)	350	84.29	-	<LOD	<LOD	^{Footnote F}	1.4^{Footnote E} (0.52-2.3)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 12.2.2 - Malathion dicarboxylic acid (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2518	82.93	-	<LOD	<LOD	0.42 (0.37-0.48)	0.95^{Footnote E} (0.40-1.5)
Males, 3-79 years
4 (2014-2015)	1256	83.13	-	<LOD	<LOD	0.35 (<LOD-0.45)	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1262	82.73	-	<LOD	<LOD	0.46 (0.31-0.61)	^{Footnote F}
3-5 years
4 (2014-2015)	499	80.76	-	<LOD	<LOD	1.1^{Footnote E} (0.68-1.5)	^{Footnote F}
6-11 years
4 (2014-2015)	509	79.41	-	<LOD	<LOD	^{Footnote F}	2.1^{Footnote E} (0.87-3.2)
12-19 years
4 (2014-2015)	501	82.83	-	<LOD	<LOD	0.32 (<LOD-0.42)	0.48 (0.31-0.65)
20-39 years
4 (2014-2015)	357	89.08	-	<LOD	<LOD	0.32 (<LOD-0.42)	0.50^{Footnote E} (0.19-0.80)
40-59 years
4 (2014-2015)	302	83.77	-	<LOD	<LOD	0.42^{Footnote E} (<LOD-0.64)	^{Footnote F}
60-79 years
4 (2014-2015)	350	84.29	-	<LOD	<LOD	^{Footnote F}	1.7^{Footnote E} (0.82-2.6)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

13 Summary and results for parabens

13.1 Parabens

Parabens are a group of para-hydroxybenzoic (p-hydroxybenzoic) acid esters, four of which were measured in cycle 4 of the Canadian Health Measures Survey (CHMS): methyl, ethyl, propyl, and butyl paraben.

Table 13.1.1 - Parabens measured in the Canadian Health Measures Survey cycle 4 (2014-2015)
Paraben	CASRN
Methyl paraben	99-76-3
Ethyl paraben	120-47-8
Propyl paraben	94-13-3
Butyl paraben	94-26-8

Parabens are widely used as preservatives in cosmetic and personal care products owing to their antibacterial and antifungal properties (Health Canada, 2016h). These products include makeup, moisturizers, sunscreens, hair-care products, facial and skin cleansers, and shaving products. Methyl, propyl, and butyl paraben are the most common ones used in cosmetic products (FDA, 2007). Typical concentrations of parabens in cosmetic products are generally 0.3% or less (Health Canada, 2016h). Parabens are also used as preservatives in food products, beverages, and pharmaceutical drugs (Ye et al., 2008). Propyl paraben and butyl paraben are classified as natural health products (NHPs) as they can be used as a source of p-hydroxybenzoic acid, a major metabolite of parabens (Health Canada, 2016b).

Although parabens in commercial use are synthetically produced, some parabens also occur naturally as preservatives in certain fruits and vegetables, such as blueberries and carrots (Health Canada, 2016h). Production and use of paraben-containing products can result in their release to the environment through various waste streams. A potential route of exposure for the general public is dermal contact with products such as moisturizers and cosmetics that contain parabens. Approximately 50% of cosmetics in the United States contain parabens with methylparaben being the most commonly used and lipstick having the highest concentrations (Cosmetic Ingredient Review Expert Panel, 2008; Yazar et al., 2011). Oral exposure to parabens can also occur via consumption of foods or pharmaceuticals containing parabens, ingestion of breast milk, and ingestion of house dust (CDC, 2009; Fan et al., 2010; Ye et al., 2008).

Dermal exposure may result in small amounts of parabens being absorbed. Following oral exposure, parabens are rapidly absorbed from the gastrointestinal tract (NTP, 2005b). Once absorbed, parabens are mainly hydrolyzed to p-hydroxybenzoic acid that can then be conjugated with glycine, glucuronide, and sulphate for excretion in urine (Soni et al., 2005). Currently, there is no evidence of bioaccumulation potential in humans. In laboratory animals, complete elimination of orally ingested ethyl and propyl paraben was observed within 72 hours (Soni et al., 2005). Data are limited in humans, with one study of premature infants observing excretion, primarily in the conjugated form, of approximately 10% to 90% of a methyl paraben dose (Hindmarsh et al., 1983). A recent study of parabens in urine of 100 adults found that parabens in urine appear predominantly in their conjugated forms (Ye et al., 2006). The concentration of parabens in urine (conjugated and free) can be used as a biomarker of exposure to parabens. As p-hydroxybenzoic acid is a nonspecific metabolite of all parabens, it may not be an optimal biomarker of exposure for specific parabens.

Health effects from low-level exposures to parabens are unknown; no acute, subchronic, or chronic toxicity has been observed (Cosmetic Ingredient Review Expert Panel, 2008). Animal studies have found parabens to be non-allergenic, however, sporadic human cases of anaphylactic reactions have been reported following paraben exposure. Parabens have been found to weakly mimic estrogens in animal studies. However, safety assessments of maximum estimated paraben exposure have concluded that estrogenic effects are unlikely in humans. Parabens have not been found to be animal carcinogens and neither Health Canada nor the International Agency for Research on Cancer has evaluated parabens with respect to human carcinogenicity.

Methyl, ethyl, propyl, and butyl paraben were included in the categorization of the Domestic Substances List carried out under the Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada, 1999; Canada, 2007). None of the four parabens was categorized as a priority substance for future assessment based on environmental or human health criteria; however, a screening level risk assessment is planned (Environment Canada, 2013b). Health Canada has reviewed the current available evidence on risk posed by parabens when used in cosmetics and does not have any health or safety concerns with these ingredients in their present practices of use (Health Canada, 2016h). Health Canada continues to monitor and review any new scientific data on parabens (Health Canada, 2016h).

Parabens were measured in a 2011 biomonitoring study carried out in Alberta with 39 participants aged 12-67 years who were patients at a primary care clinic specializing in environmental health sciences (Genuis et al., 2013). The 50^th percentile urinary concentrations measured in this study were 25.95, 10.30, 2.80, and 0.32 µg/L for methyl, ethyl, propyl, and butyl paraben, respectively.

Methyl, ethyl, propyl, and butyl paraben were analyzed in the urine of Canadian Health Measures Survey participants aged 3-79 years in cycle 4 (2014-2015). Data are presented as µg/L and µg/g creatinine. Parabens were also measured in cycle 3 (2012-2013); however, the data are not yet available because of ongoing quality assurance confirmation of the biospecimen analysis. Finding a measurable amount of parabens in urine is an indicator of exposure to parabens and does not necessarily mean that an adverse health effect will occur.

Table 13.1.2 - Methyl paraben - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2564	8.39	17 (13-22)	<LOD	15 (9.8-20)	270 (190-340)	490 (340-640)
Males, 3-79 years
4 (2014-2015)	1275	10.51	9.4 (6.9-13)	<LOD	6.8^{Footnote E} (4.2-9.4)	^{Footnote F}	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	6.28	30 (21-43)	1.8 (1.3-2.4)	^{Footnote F}	310^{Footnote E} (170-440)	510^{Footnote E} (170-850)
3-5 years
4 (2014-2015)	511	6.26	12 (9.3-15)	1.9^{Footnote E} (<LOD-2.7)	8.0 (5.9-10)	110^{Footnote E} (50-170)	330^{Footnote E} (110-560)
6-11 years
4 (2014-2015)	514	9.73	7.6 (6.4-9.1)	1.4 (<LOD-1.8)	6.1 (4.0-8.2)	43 (30-57)	^{Footnote F}
12-19 years
4 (2014-2015)	505	8.12	14^{Footnote E} (9.1-21)	<LOD	9.7 (6.4-13)	300^{Footnote E} (130-470)	520^{Footnote E} (250-780)
20-39 years
4 (2014-2015)	362	7.18	16^{Footnote E} (9.3-28)	1.3^{Footnote E} (<LOD-1.9)	^{Footnote F}	300^{Footnote E} (170-430)	390^{Footnote E} (180-610)
40-59 years
4 (2014-2015)	312	11.22	21^{Footnote E} (11-38)	<LOD	^{Footnote F}	270^{Footnote E} (93-440)	550^{Footnote E} (250-860)
60-79 years
4 (2014-2015)	360	8.61	20 (16-26)	1.4^{Footnote E} (<LOD-2.0)	22^{Footnote E} (8.2-36)	^{Footnote F}	680^{Footnote E} (210-1200)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.3 - Methyl paraben (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2563	8.39	15 (11-21)	<LOD	13^{Footnote E} (6.5-19)	230 (180-290)	340 (230-440)
Males, 3-79 years
4 (2014-2015)	1274	10.51	7.4 (5.4-10)	<LOD	5.3^{Footnote E} (3.3-7.2)	99^{Footnote E} (<LOD-150)	230^{Footnote E} (130-340)
Females, 3-79 years
4 (2014-2015)	1289	6.28	31^{Footnote E} (21-46)	2.1 (1.5-2.7)	37^{Footnote E} (17-56)	290^{Footnote E} (180-400)	480^{Footnote E} (250-700)
3-5 years
4 (2014-2015)	511	6.26	21 (16-27)	3.7 (<LOD-4.6)	13^{Footnote E} (8.2-19)	210^{Footnote E} (72-360)	430^{Footnote E} (200-660)
6-11 years
4 (2014-2015)	513	9.73	8.4 (7.1-9.8)	1.8 (<LOD-2.2)	7.1 (5.3-8.8)	41 (30-52)	^{Footnote F}
12-19 years
4 (2014-2015)	505	8.12	9.9^{Footnote E} (6.7-15)	<LOD	7.2 (4.9-9.5)	180^{Footnote E} (66-290)	370^{Footnote E} (100-640)
20-39 years
4 (2014-2015)	362	7.18	13^{Footnote E} (6.9-25)	0.90^{Footnote E} (<LOD-1.4)	^{Footnote F}	230 (150-310)	280^{Footnote E} (94-460)
40-59 years
4 (2014-2015)	312	11.22	19^{Footnote E} (10-35)	<LOD	^{Footnote F}	250^{Footnote E} (140-370)	310^{Footnote E} (130-490)
60-79 years
4 (2014-2015)	360	8.61	20 (16-23)	1.2^{Footnote E} (<LOD-1.7)	22^{Footnote E} (13-31)	320^{Footnote E} (<LOD-510)	620^{Footnote E} (340-890)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.4 - Ethyl paraben - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2564	64.86	-	<LOD	<LOD	27^{Footnote E} (14-39)	73^{Footnote E} (33-110)
Males, 3-79 years
4 (2014-2015)	1275	71.69	-	<LOD	<LOD	11 (6.9-14)	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	58.11	-	<LOD	<LOD	39^{Footnote E} (14-64)	^{Footnote F}
3-5 years
4 (2014-2015)	511	65.95	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
6-11 years
4 (2014-2015)	514	78.79	-	<LOD	<LOD	2.0^{Footnote E} (1.1-2.9)	3.4^{Footnote E} (1.3-5.5)
12-19 years
4 (2014-2015)	505	68.91	-	<LOD	<LOD	^{Footnote F}	28^{Footnote E} (11-45)
20-39 years
4 (2014-2015)	362	54.42	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	52.56	-	<LOD	<LOD	^{Footnote F}	98^{Footnote E} (44-150)
60-79 years
4 (2014-2015)	360	58.89	-	<LOD	<LOD	38^{Footnote E} (22-55)	78^{Footnote E} (44-110)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.5 - Ethyl paraben (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2563	64.86	-	<LOD	<LOD	25^{Footnote E} (8.9-42)	59^{Footnote E} (23-95)
Males, 3-79 years
4 (2014-2015)	1274	71.69	-	<LOD	<LOD	6.5 (4.4-8.6)	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	58.11	-	<LOD	<LOD	54^{Footnote E} (22-86)	120^{Footnote E} (54-190)
3-5 years
4 (2014-2015)	511	65.95	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
6-11 years
4 (2014-2015)	513	78.79	-	<LOD	<LOD	2.0^{Footnote E} (1.2-2.8)	4.6^{Footnote E} (2.2-7.1)
12-19 years
4 (2014-2015)	505	68.91	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
20-39 years
4 (2014-2015)	362	54.42	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	52.56	-	<LOD	<LOD	41^{Footnote E} (<LOD-70)	^{Footnote F}
60-79 years
4 (2014-2015)	360	58.89	-	<LOD	<LOD	44^{Footnote E} (26-62)	70^{Footnote E} (29-110)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.6 - Propyl paraben - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2564	20.83	2.5 (1.8-3.5)	<LOD	2.0^{Footnote E} (1.2-2.7)	59^{Footnote E} (34-85)	130^{Footnote E} (67-180)
Males, 3-79 years
4 (2014-2015)	1275	26.51	1.3 (0.96-1.8)	<LOD	0.77 (0.55-0.99)	^{Footnote F}	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	15.21	4.9^{Footnote E} (3.2-7.6)	<LOD	5.6^{Footnote E} (1.9-9.4)	83^{Footnote E} (38-130)	170^{Footnote E} (58-280)
3-5 years
4 (2014-2015)	511	20.16	1.5 (1.1-2.0)	<LOD	1.2^{Footnote E} (0.67-1.7)	16^{Footnote E} (7.3-24)	^{Footnote F}
6-11 years
4 (2014-2015)	514	22.76	1.2 (0.99-1.6)	<LOD	0.95^{Footnote E} (0.58-1.3)	11 (7.8-14)	^{Footnote F}
12-19 years
4 (2014-2015)	505	18.42	2.3^{Footnote E} (1.6-3.3)	<LOD	1.8^{Footnote E} (1.1-2.4)	55^{Footnote E} (17-92)	110^{Footnote E} (56-170)
20-39 years
4 (2014-2015)	362	17.68	^{Footnote F}	<LOD	^{Footnote F}	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	19.87	^{Footnote F}	<LOD	^{Footnote F}	^{Footnote F}	^{Footnote F}
60-79 years
4 (2014-2015)	360	26.39	3.0^{Footnote E} (2.0-4.6)	<LOD	^{Footnote F}	^{Footnote F}	^{Footnote F}
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.7 - Propyl paraben (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2563	20.83	2.3^{Footnote E} (1.6-3.3)	<LOD	1.5^{Footnote E} (0.85-2.1)	63^{Footnote E} (30-96)	110 (73-140)
Males, 3-79 years
4 (2014-2015)	1274	26.51	1.0 (0.74-1.4)	<LOD	0.70 (0.46-0.93)	^{Footnote F}	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	15.21	5.1^{Footnote E} (3.0-8.5)	<LOD	^{Footnote F}	87^{Footnote E} (51-120)	160^{Footnote E} (91-230)
3-5 years
4 (2014-2015)	511	20.16	2.6 (2.0-3.4)	<LOD	1.8^{Footnote E} (1.0-2.6)	30^{Footnote E} (17-43)	68^{Footnote E} (20-120)
6-11 years
4 (2014-2015)	513	22.76	1.4 (1.1-1.7)	<LOD	1.1 (0.74-1.4)	9.1 (6.4-12)	^{Footnote F}
12-19 years
4 (2014-2015)	505	18.42	1.7 (1.2-2.4)	<LOD	1.1^{Footnote E} (0.64-1.6)	^{Footnote F}	85^{Footnote E} (42-130)
20-39 years
4 (2014-2015)	362	17.68	^{Footnote F}	<LOD	^{Footnote F}	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	19.87	^{Footnote F}	<LOD	^{Footnote F}	^{Footnote F}	96^{Footnote E} (29-160)
60-79 years
4 (2014-2015)	360	26.39	2.9^{Footnote E} (2.0-4.2)	<LOD	2.6^{Footnote E} (0.95-4.2)	^{Footnote F}	190^{Footnote E} (110-280)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.8 - Butyl paraben - Geometric means and selected percentiles of urine concentrations (μg/L) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2564	83.15	-	<LOD	<LOD	^{Footnote F}	4.3^{Footnote E} (2.0-6.6)
Males, 3-79 years
4 (2014-2015)	1275	90.12	-	<LOD	<LOD	<LOD	^{Footnote F}
Females, 3-79 years
4 (2014-2015)	1289	76.26	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
3-5 years
4 (2014-2015)	511	83.37	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
6-11 years
4 (2014-2015)	514	90.08	-	<LOD	<LOD	<LOD	1.1^{Footnote E} (0.30-1.8)
12-19 years
4 (2014-2015)	505	80.40	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
20-39 years
4 (2014-2015)	362	81.77	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	81.09	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
60-79 years
4 (2014-2015)	360	80.00	-	<LOD	<LOD	^{Footnote F}	6.8 (4.4-9.1)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Table 13.1.9 - Butyl paraben (creatinine adjusted) - Geometric means and selected percentiles of urine concentrations (μg/g creatinine) for the Canadian population aged 3-79 years by age group, Canadian Health Measures Survey cycle 4 (2014-2015).
Cycle	n	%<LOD^{Footnote a}	GM (95% CI)	10^th (95% CI)	50^th (95% CI)	90^th (95% CI)	95^th (95% CI)
Total, 3-79 years
4 (2014-2015)	2563	83.15	-	<LOD	<LOD	^{Footnote F}	4.2^{Footnote E} (1.5-6.8)
Males, 3-79 years
4 (2014-2015)	1274	90.12	-	<LOD	<LOD	<LOD	0.79^{Footnote E} (<LOD-1.2)
Females, 3-79 years
4 (2014-2015)	1289	76.26	-	<LOD	<LOD	^{Footnote F}	9.2^{Footnote E} (<LOD-15)
3-5 years
4 (2014-2015)	511	83.37	-	<LOD	<LOD	^{Footnote F}	3.1^{Footnote E} (<LOD-5.1)
6-11 years
4 (2014-2015)	513	90.08	-	<LOD	<LOD	<LOD	0.81^{Footnote E} (0.30-1.3)
12-19 years
4 (2014-2015)	505	80.40	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
20-39 years
4 (2014-2015)	362	81.77	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
40-59 years
4 (2014-2015)	312	81.09	-	<LOD	<LOD	^{Footnote F}	^{Footnote F}
60-79 years
4 (2014-2015)	360	80.00	-	<LOD	<LOD	4.2^{Footnote E} (<LOD-6.5)	6.7^{Footnote E} (2.1-11)
^a If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated. ^E Use data with caution. ^F Data is too unreliable to be published.

Footnotes

Footnote a

If >40% of samples were below the LOD, the percentile distribution is reported but means were not calculated.

Return to footnote a referrer

Footnote b

Data not available as participants under the age of 6 years were not included in cycle 1 (2007-2009).

Return to footnote b referrer

Footnote c

For each individual within a cycle, the sum of arsenate, arsenite, dimethylarsinic acid, and monomethylarsonic acid is calculated. If the value of a species is less than the limit of detection (LOD), then the imputed value calculated as LOD divided by 2 is used. If all four arsenic species are reported as less than the LOD, then the sum will be the sum of the four imputed values.

Return to footnote c referrer

Footnote E

Use data with caution.

Return to footnote E referrer

Footnote F

Data is too unreliable to be published.

Return to footnote F referrer

Footnote X

Suppressed to meet the confidentiality requirements of the Statistics Act.

Return to footnote X referrer

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Date modified:: 2020-12-18

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