stewart kowalczyk
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Disposal, discovery & disruption:
subsurface vapour transport & impacts of chlorinated solvents in a local community
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Dr Alex G Stewart, Health Protection Physician, Public Health England, LiverpoolMr George Kowalczyk, Principal Toxicologist, wca-environment, Faringdon, Oxfordshire
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Mersey basin
Source: http://www.penketh.com/overhead/runcorn.jpg
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2.6M peopleIndustry & Pollution
Population By PCT
233,000 to 254,000 (2)177,000 to 233,000 (3)150,000 to 177,000 (4)115,000 to 150,000 (3)
81,000 to 115,000 (3)
Central Liverpool
~1/6 living on PCL
Halton
42% residences within 50m of PCL
PCL = Potentially Contaminated Land
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2.6M peopleIndustry & Pollution
Population By PCT
233,000 to 254,000 (2)177,000 to 233,000 (3)150,000 to 177,000 (4)115,000 to 150,000 (3)
81,000 to 115,000 (3)
Central Liverpool
~1/6 living on PCL
Halton
42% residences within 50m of PCL
PCL = Potentially Contaminated Land
PM10
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Disposal
Old Lagoon Level
Landfill in old quarry
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North & South Quarries
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Dispersion?
Old Lagoon Level
Landfill in old quarry
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Surveillance & Investigation
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Old Lagoon Level
Sample pore water & geological investigations
Analyse water for:pHconductivityHCBDVOCsNaCa
Landfill in old quarry
Up to 6.8 ppbin
26 homes
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HCBD found
Reference level (COT) <0.6 ppb
© AGS
HCBD : Review of toxicology and risk assessment
George Kowalczyk, Principal Toxicologistwca-environment, Faringdon, Oxfordshire
BACKGROUND
Used as a solvent and hydraulic fluid
Waste by–product of chlorinated solvent manufacture
TOXICITY
Exposure to HCDB
• causes kidney damage (renal proximal tubules)
• produces kidney tumours at much higher doses
HCBD itself is not nephrotoxic• active toxic species is metabolite arising from β- lyase cleavage of a cysteine conjugate of HCBD
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Metabolism Amount of active metabolite determined by…….
1.Uptake and distribution (determined by physico-chem properties)
2 MetabolismLIVER– Glutathione S-transferases – to generate CYSTEINE Conjugate
KIDNEY– β lyase – ACTIVATES toxic species from CYSTEINE conjugate– N-acetyl transferase -DETOXIFIES (mecapturic acid derivative)– Renal acylase - regenerates CYSYEINE conjugate
β‐lyase cleaves C-S bond to generate toxic species
Cytosolic and mitochondrial types
Mitochondrial activity has impacts upon respiratory chain
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HCBD metabolism
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HCBD metabolism
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Glutathione conjugate formed in LIVER
Transported to KIDNEY where converted by ß lyase (a kidney tubule specific enzyme) to an electrophilic agent
Causes kidney lesions in proximal convoluted tubules, possibly by binding to ά2 microglobulin, resulting in tissue necrosis
rodent specific pathway ?
CoT evaluation
Animal NOAEL (rat ) is 0.2 mg/kgbw/day ‐ equivalent to 60 ppb in air (PoD)
Human dose of 0.6 ppb ‐margin of exposure (MoE) of 100 above rat NOAEL
0.6 ppb is an exposure which is 10,000 lower than a carcinogenic dose in rats
0.6 ppb considered to present a minimal carcinogenic risk to humans
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PBPK modelling approach Comparison with rodents
•Glutathione conjugation 5 x lower in man
•β lyase activity 3x lower in man
•N‐acetyl transferase activity 3.5 x lower inman
•Acylase activity zero in man
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(Green et al Tox Letters 2003)
PBPK modellingActivity of key enzymes 20-40 times higher in rat than humans
Exposure in rats produces more of active metabolite per dose received
NOAEL (rat) = 0.2 mg/kg bw/ d converted to 70 ppb in air
70 ppb in rats produces 137.7 mg/l of active metabolite
(Green et al 2003)
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Rat EXPOSURE 70ppb
ACTIVE METABOLITE
137.7mg/l
Human EXPOSURE 1400ppb
ACTIVE METABOLITE
137.7mg/l
PBPK based PoDPoD from PBPK model is 1400 ppb
UNCERTAINTY FACTORS – Animal to Humans (default=10)
UF for interspecies toxicokinetics (levels of key metabolite) =1 (default is 4.0)
UF for interspecies toxicodynamics (is metab more toxic in man than rat?) = 2.5
UNCERTAINTY FACTORS - HUMAN VARIABILITY (default=10)
UF for human kinetics (variability in levels of metabolites) = 3.2
UF for human dynamics (variability in response) =3.2
Total UF = 25 (1 x2.5 x 3.2 x 3.2)
TDI = 1400/25 = 56 ppb (ie several times higher than levels experienced in homes)
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Canada - BMD approachEvaluation by Environment Canada based on Benchmark Dose Approach
BMR = 5 % level of kidney effects ‐ 2 year rat study (same as used by CoT)
BMDL05 = 0.035 mg/kg bw/d = 10 ppb continuous
Applying total UF of 100 to this PoD = 0.1 ppb as HCV
WHICH HCV????
• Canada = 0.1 ppb
• CoT = 0.6 ppb
• PBPK = 56 ppb
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Health studies
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North Quarry only
Polluter pays:-evacuation,
affected housesbought
& demolished
Routine Tests
Full clinical examination
Standard investigations
Urine tests
Proximal kidney tubule damage => enzyme release
Looked for these enzymes in urine
Not specific for effects of HCBD
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HCBD metabolism
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Kidney nephron
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Urinary markers
Urinary Marker Site of damage / dysfunction Reference range
α glutathione-S- transferase(alpha GST)
Proximal tubular cell damage <2.2μg/mmol
Albumin Glomerular permeability <3.5mg/mmol.
γ-glutamyl transferase (GGT) Proximal tubular cell damage < 6.0iu/mmol
Leucine aminopeptidase (LAP) Proximal tubular brush border cell damage
<0.8iu/mmol
N-acetyl-β-glucosaminidase(NAG)
Proximal tubular damage <1.25iu/mmol
π glutathione-S-transferase(pi GST)
Distal tubular cell damage <5.8μg/mmol
Retinol binding protein (RBP) Proximal tubular reabsorption <22μg/mmol
Total urinary protein Interpret in conjunction with albumin <13.5mg/mmol
Transferrin Glomerular permeability <0.36iu/mmol
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HCBD metabolism Results of urinary markers of early renal dysfunction. Each result is
expressed as a proportion of the upper limit of the adult reference range.
0
2
4
6
8
10
alpha GST Albumin GGT LAP NAG Pi GST RBP T. Protein T'ferrin
Distal
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Comparison of number of elevated proximal tubular markers in first and second round of tests
(Age 16-65)
1714
5
1
30
42 1
0
5
10
15
20
25
30
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0 1 2 3
Number of elevated results per person
Freq
uenc
y co
unt
Series1 Series2
ElevatedSeries 1: 20/37 (54%)Series 2: 7/37 (18%)
Suggests - some people who had health checks may have been exposed to something which has had an effect on kidney function.
Staples et al, Occupational & Environmental
Medicine 2003; 60 (7) 463-467
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Conclusion
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Sl
ide
Source: PINS & CPAD Inpatient Databases
Caveats: NW renal disease
1990 to 1996
Age Standardised Renal Ratio
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Caveats: Local renal disease
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Caveats: Other causes?
HCBD or something else?
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1,2-dichloroethane 1,4 dioxane1-chloro-2,3-epoxypropaneAcetaldehydeAcrylonitrileArsenicCadmiumCarbon tetrachlorideChloroformChloromethaneCopperDimethyl sulphate
Ethylene oxideHalons (all types)LeadManganese Mercury (Hodgson et al, OEM 2004, 2007; AJE 2007)
PhenolSeleniumTetrachloroethene TrichloroethyleneTrichlorotolueneXylene (all isomers)
23 renal toxins; 28 chimneys
Caveats: Other sources
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Feared consequences of exposure gives greater public reaction than any likelihood of exposure
• Stress, anxiety, worry
• Strained relationships:• Family• Friends• Colleagues
• Community conflict and division
• Stigmatism “The Village of the Damned”
Barnes. Social Science & Medicine 2002; 55: 2227-2241Stewart et al. Int. J. Environ. Res. Public Health 2010, 7, 1153-1173
personal
national
Psychological & Social Effects
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AcknowledgementsDr Brian StaplesDr John ReidMr George Wilkinson
Chlorinated solvents in a local community
Thanks for listening.
Any questions?
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