Human exposure through the environment 2010

1 Human environmental exposure Martin van den Berg Institute for Risk Assessment Sciences Utrecht University Primary routes of human exposure to chemicals  Dust and vapor inhalat

1

Human environmental

exposure

Martin van den Berg Institute for Risk Assessment Sciences

Utrecht University

Primary routes of human

exposure to chemicals

  Dust and vapor inhalation

  Dermal contact with contaminated soil or dust

  Ingestion of contaminated food, water, dust or soil

  Predominant route is inhalation or dermal contact

  Minor dust ingestion and hand to mouth contact

The environmental pathways to human

exposure (Paustenbach 2002)

Concepts of exposure and dose

!   Actual contact of the organism

!   Actual entry of the chemical (crossing a

boundary)

availibility and amount of chemical that

is toxicological relevant

influenced by body distribution factors

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Crossing the boundary from the

“outside to the inside”

  Physical movement

from the chemical by

inhalation, eating or

drinking

  Chemical contained

in medium such as

food, soil, dust or

water

  Physical uptake and transport across a boundary in the body (e.g skin or GI-tract) that is a cell layer

  Transport medium is usually not absorped with same rate as the chemical Bioavailability

Lipophilicity

Concept of applied, potential and

internal dose

  Amount of chemical

available at the

absorption barrier

(e.g lung, GI

tract,skin)

dose:

  This is the difference with applied dose

  This is the toxicological relevant parameter after body

distribution has been taken into account

Biological relevant dose (BED) is

ultimate goal for exposure assessment !

Xeno-estrogens

and kinetics

Integrated exposure Area under the curve (AUC)

!   Identification of:

Determining (Lifetime) Average Daily Dose

(LADD and ADD)

5 Time weighted average dose

(Lifetime) average daily dose (L)ADD

Quantifying Exposure

 Integrating exposure concentration and

time of contact

 Hypothetical exposure, but realistic

 Using internal indicators: biomarkers,

excretion levels, body burden

Gasses Occup exposure

Worst case

Types of biomonitoring sampling

!   Method

!   Breath

!   Blood

!   Adipose

!   Nails, Hair

!   Urine

!   Blood, urine, hair

!   Example

!   Volatile organics, alcohol;

!   Lead, pesticides, heavy metals

!   Chlorinated pesticides, dioxins

!   Heavy metals

!   Tetra/trichloro-ethylene

!   Drugs, pharmaceuticals

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Obtaining Uptake and Intake data

 Drinkingwater consumption

 Consumption fruit, vegetables, beef, dairy etc

 Consumption recreation caught fish

 Incidental soil ingestion rate

 Effective surface area of the body

Hormones

Lipophilic compounds

Pesticides

Lipophilic compounds

Some standard assumptions for exposure (EPA 1996)

Direct and indirect exposure pathways

An example Municipal Incinerators

(D Paustenbach et al, 2002)

Dioxins and

heavy metals

Bioavailibility

Breastmilk

Dioxins in foodstuff in the Netherlands and

effect of lifestyle (Liem and Theelen, 1997)

Dutch Turks

General Dutch population

1 % or more of Turks exceeds 10 times the WHO TDI

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Percentage of Dutch population exceeding the TDI of

dioxin in The NL (Liem and Theelen 1997)

> 80% exceeds WHO TDI

1-1.5% exceeds 10x WHO TDI More than 150.000 people Infant

Influence of animal (dairy) products on the exceedence

in the Dutch population (Liem and Theelen,1997)

Aslight increase e.g from 4 to 5 pg TEQs/

g fat means a few % of the Dutch population exceeds TDI and involves easily more than 100.000 people

What are background levels?

!   “Pristine” levels: Not similar to background levels as areas

without anthropogenic influence do not exist anymore on this

planet

!   “Normal” levels: Average levels that are found e.g in rural areas

without significant influence of industry, traffic or geochemical

anomalies

!   “Historically polluted regions”: E.g densely populated regions

that have been polluted by e.g industry, mining and traffic

!   Geochemical variation: Background “natural” levels of toxic

elements (e.g heavy metals) may vary with regions due to

geochemical variations (e.g arsenic in the US)

Dermal transport of chemicals

!   Major determinants: solubility (Kow) and

matrix/medium (bioavailability)

!   Transport inverse function of molecular

weight and volume

Consequence: hydrophobic agents with low MW

permeate better than hydrophilic agents with high

MW For small molecules hydrophobicity major

factor dermal penetration

!   Lipophilic compounds tend to

accumulate in stratum corneum

!   Decreasing Permeability: foot/sole >

palm > scrotum > forehead > abdomen

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Estimation of uptake via the skin

(Fick’s law of diffusion at steady state)

!   Partition parameter Kp is key parameter and

be approached with Kow

Key factors that influence dermal uptake of

xenobiotics from the environment

!   Bioavailability: large impact on uptake and depends on the

organic content soil

!   Skin surface area: use rule of “nines” 9 percent for head and

neck and each upper limb 18 percent for each lower limb Front

of back of the trunk also each 18 percent US EPA estimates

exposed area of 2900, 3400 and 2940 cm2 for children from 0-2

and 2-6 years, and adults

!   Actual soil loading on the skin: 0.5-6 mg/cm2 and 0.2 to 2.8 mg/

cm2 for adults and children

Calculation of dermal

uptake of chemical in

gaseous or aqueous

media (Paustenbach 2002)

Human cutaneous permeability

coefficients (cm/h)

in aqueous medium

(From Paustenbach 2002)

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Representative surface area’s of the male human body (Paustenbach 2002)

US-EPA suggested method for percutanous absorption from soil:

An example: Skin uptake of a chemical from water

(from Paustenbach 2002)

!   Soil ingestion

!   Indoor and outdoor exposure

!   Varies strongly with age,

most significant between 2

and 7 years

!   Uptakes varies between

several mg/d for adults up to

many 100’s mg/d for children

(Pica)

!   Bioavailibility is a significant

parameter for eventual risk

!   (Table from Paustenbach

2002)

!   Estimating intake via food

!   Limit expressed as ADI or

TDI (gram unit/kg bw – day)

!   Lifestyle is major uncertainty

in determining actual uptake

for the population

!   Lipophilic contaminants

mostly via dairy, meat and

fish

!   Uptake pesticides also

through vegetables and fruit

!   (Table from Paustenbach

2002)

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!   Breast milk – a special situation

!   TDI or ADI not applicable (no life time exposure)

!   Accumulation of lipophilic compounds (e.g PCBs, dioxins) and drugs

!   Disadvantages and advantages

!   (Table from Paustenbach 2002)

!   Intake via inhalation – relative small numbers of uncertainty

!   Most significant variables: inhalation rate, airborne chemical

concentration, bioavailibility and particle size

!   Major differentation between gases and particles with adsorped

contaminants (bioavailibility)

!   (Table from Paustenbach 2002)

Particle size inhalation

!   Major disposition areas:

  Nasal or Oral region

  Trachea region

  Bronchial region

  Alveolar region

Disposition of particles in respiratory tract

!   Major deposition ways:

!   Particle clearance:

  1) GI tract, 2) lymphatics and lymph nodes,

3)pulmonary vasculature -> venous circulation

!   Nasal clearance:

  Swallowing, wiping, blowing

!   Trachealbronchial clearance:

  Coughing, upward movement, swallowed

!   Pulmonary clearance:

  Upward movement mucociliary escalator

  Phagocytized by macrophages cleared by

mucociliary escalator

  Phagocytized by alveolar macrophages

removed by lymphatic drainage

  Dissolvement from surfaces particles and

removed by bloodstream or lymphatics

  Direct penetration small particles epithelial

membranes -> blood or lymphatics

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Institute for Risk Assessment Sciences Prof dr Martin van den Berg

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University of Utrecht

Increasing exposition

Safety standard

air/product No effect animal

Lowest effect

Safety margin 100 1/10 inter humans * 1/10 animals -> humans

Harbor personel

(not protected)

Wharehouse personel

(not protected)

Consumers

?

Methylbromide/Dichloorethaan in containers:

Interpretation measurements ZfAM (Germany/Netherlands)

Increasing exposition

Lowest effect

Safety margin

?

Methylbromide: Exposure and Effects

human

Acute – high:

Death, coma, seizure, lung, hart and vascular damage, strong neurological and behaviorial effects, kidney/stomach effects

Acute – low:

Mild neurological and behavioral effects, lung and stomach damage

Chronic– low:

Irritation lungs (inhalation)

and GI tract(oral),

mild neurological and

behavioral effects

Chronic-high:

Lung, heart and vascular damage, strong neurological and behavioral effects kidney/stomach effects

Consumer/employer

Employer

Most important for

unprotected consumers

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Prof dr Martin van den Berg

Safety standard

air/product No effect animal

Veiligheids marge

?

Dichloorethaan: Exposure and Effects

Consumer/employer

Death, depression central nervous system, asphyxiation heart, liver, kidney and brain damage, general sedation

Acute – low:

Mild effects Central nervous system Respiration, cardiac rhythm mild sedative effect

Chronic - low:

Effect on heart and

Respiration and nervous

system, carcinogenic?

Chronic-high:

Depression central nervous system and respiration,heart, liver,kidney and brain damage,

carcinogenic ?

Most important for

sensitive unprotected

consumers

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Prof dr Martin van den Berg

Increasing exposition

Lowest effect human

Safety standard

air/product No effect animal

Contamination consumer products from containers

result from different sources!

Cheap and old fashioned Production process with

benzene en toluene

Outside Europe en N-America

Fumigation with

methylbromide

and dichloroethane

Exceeds safety standard

consumer

in a chemical cocktail

+

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Prof dr Martin van den Berg

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Protection consumer from public health point of view

(precautionary principle?)

•  No action is no option due to measurable risks for both employers

and consumers (e.g methylbromide in cacoabutter, benzene in

matrasses….)

•  Most logical legislation:

–  No use methylbromide, dichloroethaan with food products (FAO) and

‘close contact’ consumer products with synthetic foam

•  Continuation fumigation food products and “close contact” consumer

producten use a sticker for consumer warning about possible risks

Bijv:

•  The use of fumigation of pharmaceutical never allowed!

–  Risk of damaging the quality of the reactive part of

the pharmaceutical by the methylbromide

This product is fumigated and possibly damages your health and the environment

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Prof dr Martin van den Berg

Some significant issues in exposure assessment

!   Bioavailability – relevant for food, soil and airborne particles

!   Chemical fate – (bio)degradation e.g by sunlight, oxidation,

hydroxylation and microorganisms

!   Biomarkers and molecular epidemiology – e.g Proteins, RNA,

DNA and their adducts

!   What is the toxicological relevance?

!   With increasing molecular and biochemical techniques (e.g

genomics and proteomics) more identification of biomarkers, but

how relevant are these effects with respect to the real observed

adverse dose response relationships

A definite must for the risk assessment!

Human and Ecological Risk Assessment

Theory and Practice

By Dennis J Paustenbach (Wiley-Interscience, New York, 2002)