Risk Assessment II

Dec 9, 2009

Is there a “safe” dose ?

For effects other than cancer:

Dose-Response

Dose

Increasing Response

0Threshold

Non-carcinogens

No

Observed

Adverse

Effects

Level

NOAEL

ACCEPTABLE DAILY INTAKE (ADI) or TOLERABLE DAILY INTAKE (TDI)

The amount of a substance that can be ingested over a lifetime without significant health risk

ADI = NOAEL Safety Factor(s)

Poor quality of data

Safety Factor = 10 x 10 [x 10] [x 10]Inter-speciesAnimal-to-human Intra-species Particularly

inter-individual severe effectvariability

Units: mg/kg/day

Based on most sensitive species and most sensitive end-point

Extrapolations

• From short-term studies to lifetime exposure

• From high doses in animal studies to low doses in environmental exposure

• From animals to humans

Scale from animal to human

• Scale according to body weight (BW)

• Scale according to surface area – (BW)2/3

• Scale according to relative metabolic rates – (BW)3/4

• Biological modeling – physiologically-based (PBPK)

Variability • Inter-individual

variation in – Exposure– Metabolism– Repair capacity– Sensitivity– …

Uncertainty: Factors that we do not know or understand fully (yet)

• True magnitude of– Exposure– Metabolism– Repair capacity– Sensitivity

• How to extrapolate from test animals to humans, high to low doses…

• How to combine risks

Carcinogens: There exists a “measurable” risk from any exposure,

eg 4.1 x 10 -6 cancer risk for exposure to 1 μg/m3 of CH2Cl2 for a lifetime

Non-carcinogens: A “safe” dose can be determined

Pathogens: An “infectious dose” can be determined- ID50, , - Dose that produces 1 in 104 risk of infection

Each is considered in isolation

Approach has been chemical by chemical.Multiple chemical exposure requires combined risk assessment approach. Multiple sources of exposure need to be accounted for.

Combinations

• Binary mixtures

• Ternary mixtures

• Four- , five-component mixtures

• Six, seven, eight….

• ...

• Complex mixtures

The Risk Cup• Food Quality Protection Act (1996)

– Amendment to Food Drugs and Cosmetics Act (1906, 1938)

• “Assess the risk of the pesticide chemical residue [to infants and children] based on…available information concerning the cumulative effects on infants and children of such residues and other substances that have a common mechanism of toxicity”

Interactions

• Additivity

• Synergism

• Potentiation

• Antagonism

Interactions can be expected between chemicals that

• Act by binding to the same receptor

• Act through the same mechanism

• Require the same enzyme for activation/detoxication

Additivity

• Chemicals A, B, C…N are all toxic

• Potency of mixture = Sum of potencies * concentrations of constituents

• Effecttotal = PotencyA * DoseA + PotencyB * DoseB + PotencyC * DoseC +…..+PotencyN * DoseN

Synergism

• The whole is greater than the sum of the individual constituents

Effecttotal >> PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN

Potentiation

• One constituent A is toxic, the other B is not.

• Effect of the combination A + B is greater than the effect of the active constituent

Effecttotal >> PotencyA* DoseA

where PotencyB = 0

Antagonism

• Effect of the whole is less than the sum of the effects of the individual components

Effecttotal << PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN

• Competing risks

Drinking water disinfectant by-products

↔ infectious diseases

Comparison of Risks

DisabilityAdjustedLifeYears

One DALY = 1 lost year of healthy lifeDisability is weighted by a factor that reflects the severity of the disease on a scale from 0 (perfect health) to 1 (equivalent to death). WHO Global Burden of Disease analysis http://www.who.int/healthinfo/global_burden_disease/en/index.html

Some examples of weighing factors

• Asthma -- 0.043• Blindness – 0.600• Cancer: Liver – 0.20• Cancer: Trachea, bronchus and lung 0.15

– Metastatic 0.75

• Cirrhosis of the liver - 0.330• Cleft palate - Cases 0.103• Diarrheal diseases - 0.105• Malaria - 0.191

USA, Both sexes, National Center for Health Statistics

Life expectancy at birth

Year of birth

Age at death

Year of birth

Age at death

1900 47.3 1980 73.7

1950 68.2 1990 75.4

1960 69.7 2000 77.0

1970 70.8 2005 77.8

2007 77.9