Evidence on the carcinogenicity of disinfection byproducts in drinking water and pools, and public health actions Eau de boisson & santé: De l’acquisition des connaissances à la hiérarchisation des risques 14 décembre 2011, Paris
Manolis Kogevinas, MD, PhD Centre for Research in Environmental Epidemiology, Barcelona and National School of Public Health, Athens
Outline • Some history and context • Epidemiological evidence on DBPs (Disinfection By-products) and cancer, • Genetic polymorphisms and mechanisms • What do we do when a positive public health intervention may also carry some risk?
Water chlorination has been among the first major public health interventions
Percentage disability adjusted life years (DALYs) attributable to ten risk factors in developed and developing countries, 1990. Global burden of disease study, WHO
Murray & Lopez, Lancet 1997
Health effects of arsenic in drinking water Art exhibition Dhaka, Bangladesh
Disinfection by-products (DBPs) Disinfectant (e.g. chlorine) + organic matter à DBPs Ø First detected in 1974 Ø Complex mixture ≈ 700 compounds Ø Trihalomethanes (THM): CHCl3, CHCl2Br, CHClBr2, CHBr3 - Maximum level EU: 100 µg/L
Haloalkanes Chloroform Bromodichloromethane Dibromochloromethane Bromoform Dibromomethane Bromotrichloromethane Dibromodichloromethane 1,1,2-Trichloroethane Haloacetic acids Chloroacetic acid Bromoacetic acid Dichloroacetic acid Bromochloroacetic acid Dibromoacetic acid Trichloroacetic acid Bromodichloroacetic acid Dibromochloroacetic acid Tribromoacetic acid Other Haloacids 3-Bromopropenoic acid 2,2-Dichloropropanoic acid 3,3-Dichloropropenoic acid cis-2,3-Bromochloropropenoic acid trans-2,3-Bromochloropropenoic acid 2,3-Dibromopropanoic acid cis-2,3-Dibromopropenoic acid trans-2,3-Dibromopropenoic acid 3,3-Dibromopropenoic acid Trichloropropenoic acid 2-Bromo-3,3-dichloropropenoic acid (E)-3-Bromo-2,3-dichloropropenoic acid (Z)-3-Bromo-2,3-dichloropropenoic acid 2,2-Dichlorobutanoic acid cis-Bromobutenoic acid trans-Bromobutenoic acid 2,2-Dichlorobutenoic acid 2,3-Dibromobutenoic acid 2-Chloro-3-methylbutanoic acid Chlorophenylacetic acid 3,5-Dibromobenzoic acid Tribromopropenoic acid Halo-di-acids cis-Bromobutenedioic acid trans-Bromobutenedioic acid cis-Dichlorobutenedioic acid trans-Dichlorobutenedioic acid cis-Bromochlorobutenedioic acid trans-Bromochlorobutenedioic acid cis-Dibromobutenedioic acid (E)-2-Chloro-3-methylbutenedioic acid (E)-2-Bromo-3-methylbutenedioic acid Haloaldehydes Dichloroacetaldehyde Bromochloroacetaldehyde Dibromoacetaldehyde Trichloroacetaldehyde (chloral hydrate) Bromodichloroacetaldehyde Dibromochloroacetaldehyde Tribromoacetaldehyde 3-Bromo-4-methoxybenzaldehyde
Haloketones Bromopropanone 1,1-Dichloropropanone 1-Bromo-1-chloropropanone 1,1-Dibromopropanone 1,3-Dibromopropanone 1,1,1-Trichloropropanone 1,1,3-Trichloropropanone 1-Bromo-1,1-dichloropropanone 1,1,1-Tribromopropanone 1,1,3,3-Tetrachloropropanone 1,1-Dibromo-3,3-dichloropropanone Pentachloropropanone Dichlorofurandione 1-Chloro-2-butanone 1-Bromo-2-butanone Tetrachlorohydroquinone Halonitromethanes Dibromonitromethane Haloamides Dichloroacetamide Bromochloroacetamide Dibromoacetamide Bromodichloroacetamide Dibromochloroacetamide Tribromoacetamide Haloalcohols 2,2,2-Trichloroethanol 1,1,1-Trichloropropanol Other halogenated DBPs 3-Chlorobenzeneacetonitrile 2,6-Dichloro-4-methylphenol 2-Bromo-4-chlorophenol Trichlorophenol Bromodichlorophenol Tribromophenol 2-Bromo-4-chloro-6-methylphenol Dibromomethylphenol 2,4-Dibromo-1-methoxybenzene 2,3,4-Trichlorobenzeneamine Dibromochloroaniline 2-Bromo-4-chloroanisole 3,4,5-Tribromo-1H-pyrazole 2,6-Dibromo-4-nitrophenol 2,6-Dibromo-4-nitrobenzeneamine Non-halogenated DBPs/contaminants Propionamide Benzaldehyde Benzoic acid methyl ester Benzeneacetonitrile Phthalic acid Diethylphthalate Benzophenone Halonitriles Bromoacetonitrile Dichloroacetonitrile Bromochloroacetonitrile Dibromoacetonitrile Trichloroacetonitrile
More than 100 DBPs (disinfection byproducts) identified in 2 swimming pools in Barcelona (Richardson et al, EHP 2010)
Outline • Some history and context • Epidemiological evidence on DBPs (Disinfection By-products) and cancer, • Genetic polymorphisms and mechanisms • What do we do when a positive public intervention may also carry some risk?
Main DBPs and IARC classification – animal studies Trihalomethanes (THMs) Chloroform (CHCl3) Bromodichloromethane (CHBrCl2) Chlorodibromomethane (CHBr2Cl) Bromoform (CHBr3) Haloacetic acids (HAA) (C2O2HX3) Dichloro AA Trichloro AA Chloral (C2H3O2Cl3) Chloramine Hypochlorite salts Sodium chlorite Halogenated acetonitriles MX (3-chloro-4-(dichloromethyl)-5hydroxy-2(5H)-furanone)
IARC Animal
IARC Overall
S S L I
2b 2b 3 3
S L L I I I I L
2B 3 3 3 3 3 3 2B
Mutagenicity in Salmonella TA100 –S9 of a water sample from the chlorinated pool, Barcelona. Data in the curve are from a single experiment performed with one plate per dose (Richardson, EHP 2010)
Page et al, Science 1976; 193:55-57
Exposure routes Ingestion (water, coffee, tea, water-based food and beverages) All disinfection byproducts
INTERNAL DOSE
Exposure routes Inhalation
Ingestion
(shower, swimming pool, etc.) Volatile DBP e.g. THMs
(water, coffee, tea, water-based food and beverages) All disinfection byproducts
TOTAL INTERNAL DOSE
Dermal absorption (swimming pool, bath, etc.) Permeable DBPs e.g. THM, haloketones, …
Water use – Mother-child cohort (Rhea study) in Crete (Patelarou, OEM 2010)
Epidemiological evidence on cancer and DBPs ♦
Bladder: very consistent evidence
Colon: several positive studies but weaker evidence ♦
Inconsistent evidence ♦ Pancreas ♦ Brain ♦ Oesophagus ♦ Breast
…
0.6 0.4 0.2 0.0 -0.2
log (odds)
0.8
1.0
1.2
Pooled analysis. Bladder cancer risk and average exposure to trihalomethanes (THMs), both sexes
0
20
40
60
80
100
120
average THM level, micrograms/litre
(Villanueva, Epidemiology 2004)
Spanish Bladder Cancer Case-control study
• 5 Spanish areas • 18 hospitals • Recruitment. 1998 - 2001 • Response rate. 86% • Study subjects: 1219 cases, 1274 controls 2172 men 318 women
Sources of water consumption and trends in THM (trihalomethane) levels
(Villanueva, AJE 2007)
Spanish bladder cancer. Exposure in showers and baths. Duration x THM level. Men (min/day)x(µg/l)
OR (95% CI) Ca/co
26.0 - 49.0
1.2 (0.5-2.5)
2.0 (1.2-3.4)
1.8 (1.1-2.9)
>49.0
1.0 (0.4-2.5)
2.2 (1.4-4.3)
1.8 (0.9-3.5)
1.00
1.2 (0.9-1.6)
THM (µg/l) ≤8.0
all
P-value interaction: 0.02 N= 680 cases, 714 controls
Cantor. EHP 2010
Biomarkerbased Swimming Pool Study, Barcelona (PISCINA study)
PISCINA study, Main design Swim in a chlorinated pool
1 week without swimming (wash-out)
40 min
Exhaled air Blood Urine Exhaled breath condensate (EBC) eNO Lung function
Urine, 2 weeks after
Study population Inclusion criteria - 18-50 years old - Non current smokers - Non asthmatics N=50 volunteers (48 for respiratory outcomes; 34 for transcriptomics)
Biomarkers of genotoxic effects • Micronucleus assay, peripheral blood lymphocytes • SCGE -Comet assay, peripheral blood lymphocytes • Micronucleus assay, exfoliated cells in urine • Urine mutagenicity
Micronuclei
Formation of micronuclei in peripheral blood lymphocytes in relation to an increase of 1µg/m3 in THM levels in exhaled air before and after swimming. PISCINA study (Kogevinas EHP 2010)
beta coefficient and 95%CI
6 5 4 3 2 1 0 -1 -2 CHCl3
CHCl2Br
CHClBr2
CHBr3
Change in urine mutagenicity slopes in relation to an increase of 1µg/m3 in THM levels in exhaled air before and after swimming. PISCINA study (Kogevinas EHP 2010) beta-coefficient and 95%CI
5 4 3 2 1 0 -1 CHCl3
CHCl2Br
CHClBr2
CHBr3
Conclusions, PISCINA
• Strong association of exposure during swimming and some markers of genotoxicity, particulalry with brominated compounds • Positive association with urine mutagenicity, particularly with brominated compounds • Modification of these effects by genes involved in the metabolism of DBPs but low statistical power
Outline • Some history and context • Epidemiological evidence on DBPs (Disinfection By-products) and cancer, • Genetic polymorphisms and mechanisms • What do we do when a positive public intervention may also carry some risk?
IARC evaluation on the carcinogenicity of chlorinated drinking water, 1991 • Inadequate evidence for its carcinogenicity to humans (Group 3). • mainly ecological and death certificate studies available • evidence insufficient for specific byproducts
Main DBPs and IARC classification IARC IARC Animal Overall Trihalomethanes (THMs) Chloroform (CHCl3) Bromodichloromethane (CHBrCl2) Chlorodibromomethane (CHBr2Cl) Bromoform (CHBr3) Haloacetic acids (HAA) (C2O2HX3) Dichloro AA Trichloro AA Chloral (C2H3O2Cl3) Chloramine Hypochlorite salts Sodium chlorite Halogenated acetonitriles MX (3-chloro-4-(dichloromethyl)-5hydroxy-2(5H)-furanone)
S S L I
2b 2b 3 3
S L L I I I I L
2B 3 3 3 3 3 3 2B
WHO evaluation 1999
“ … Furthermore, health risks from disinfectant by-products at the levels at which they occur in drinking water are extremely small in comparison with the risks associated to inadequate disinfection.”
Public health implications: THMs and bladder cancer In view of growing evidence that exposure to disinfection by-products is associated with cancer risk and other health effects: • consideration should be given to a more strict control of contaminant levels in chlorinated drinking water • this could be achieved through water treatments that reduce the formation of such by-products without compromising the control of microbial contamination
CREAL, Water epi group
Session 1. Global Clean Water Session 2. Methods to identify DBPs Session 3. Swimming pools: Chemistry and respiratory effects Session 4. DBP Toxicology and mechanisms Session 5. Identification of emerging DBPs Session 6. Exposure assessment and evaluation of mixtures Session 7. DBP formation: Pharmaceuticals and energy extraction activities Session 8. New epidemiological evidence on DBPs, human cancer and reproductive effects Session 9. Future in research on DBPs
