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

35

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?