1

Fig. 5-1, “Toxic Triangle”, Epidemiologic Triad

Environmental Factors

Host Factors

Agents

2

Epidemiologic Triad

• Organisms• Chemicals

– exogenous– endogenous

• Nutrients• Physical

forces• Psychological

factors• Genetic

• Immunity• Immunologic

response• Host behavior

– diet

• Physical– hot, cold – altitude

• Biologic• Social

– economic

Source: Smith, Theobald, 1934

Agents Host Factors EnvironmentalFactors

Agents have characteristics such as infectivity, pathogenicity, virulence

3

Pathogens are also toxic agents that can cause cancer

• HP - Gastric; Mucosal-associated lymphoid tissue• Schistosoma haematobium - Bladder cancer• HTLV-I - Adult T-cell leukemia/lymphoma• HBV - Liver cancer• HHV-8 - Kaposi’s sarcoma• EBV - Lymphoproliferative disorders;

Nasopharyngeal; Burkitt’s lymphoma• HPV - Anogenital carcinoma; cervical cancer

• HP = Helicobacter pylori V.; HTLV = Human T-cell Leukemia/lymphoma V.; HHV = Hepatitis B V.; EBV = Epstein-Barr V.; HPV = Human papilloma V.

4

Classes of Xenobiotics

Pollutants (Air, Water, Soil)

Pesticides

Pharmaceuticals

IndustrialChemicals

FoodAdditives

Cosmetics

5

Dose - ResponseA is more toxic than B

• LD50

0

100

50

Response

Dose mg/kg

AB

6

Dose - Response• Metabolites

0

100

50

Response

Dose mg/kg

A1st Event

Intermediate

2nd Product

3rd Product

All are ActiveTargets may not be the same

7

Dose - Response• Dose related

Toxicity

0

100

50

Response

Dose mg/kg

Parathion

DDT

50080

8

Dose - Response• Modes of

Action

0

100

50

Response

Dose mg/kg

Same LD50

A

A >> Toxic at Low Dose

9

Factors Governing Toxicity

• Age– very young or old

• Strain– e.g. skin color & UV

• Gender

• Weight• Exercise and

Physical Stress• Health Status

– immune deficiencies

• The outcome of exposure to a toxin depends on a number of factors that may include:

10

Dr. Robson’s Medical Terms

Artery The study of fine painting

BariumWhat you do after CPR fails

Benign What you are after you be eight

Dilate To live longer

Morbid A higher offer

Nitrate Lower than the day rate

Tumor An extra pair

Urine The opposite of you’re out

11

ProblemContext

Risks

OptionsActions

Decisions

Evaluation

EngageStakeholdersCommunication

Throughout

The New Risk Assessment Paradigm

MostImportantStep

12

Benefits of Engaging Stakeholders

• Supports Democratic decision-making

• Ensures public values are considered

• Develops the understanding needed for better decision-making

• Improves knowledge base for decision-making

• Can reduce time & expense involved in decision-making

• May improve credibility of agencies managing risk

• Should generate better accepted, more readily implemented risk management decisions

13

Three “Laws” of Toxicology

• Dose makes the Poison– everything can create toxic effects

• Chemicals have specific effects– structure relationships, subtle changes

can mediate toxicity

• Human is an animal– animals can be used as “human”

surrogates, choice is important

14

Dose ResponseLD50

ToxicityA > ToxicityB

0

100

50

Response

Dose mg/kg

AB

15

Dose ResponseED50

EDA > EDB

0

100

50

Response

Dose mg/kg

AB

10

16

Dose ResponseNOAELNo Observable Adverse Effect Level

0

5

2

Response

Dose mg/kg7

10

50 100

Dose Response

0 0/10

7 0/10

50 2/10

100 5/10

500 10/10

500

NOAEL

17

Dose ResponseLOAELLowest Observable Adverse Effect Level

0

5

2

Response

Dose mg/kg7

10

50 100

Dose Response

0 0/10

7 0/10

50 2/10

100 5/10

500 10/10

500

LOAEL

18

Dose ResponseReference Dose, RfD• Allowable daily dose

over a lifetime• = (NOAEL) / (UF)• Uncertainty Factors

– 10x, Animals to Man– 10x, Susceptibility– 10x, Only Acute Studies– 1-10x, Others

• In absence of NOAEL– = (LOAEL) / (10)– + UF as above

• Found in EPA’s IRIS database 0

2

Res

po

nse

Dose mg/kg7 50

LOAEL

NOAEL

19

Exposure Studies

• Animal Based (surrogate for human)– Acute (high dose)

• two weeks

– Subchronic (not as high as acute)• 30 - 90 days, some less

– Long term or Chronic (lower doses)• up to two years

– Maximum Tolerated Dose (MTD)• controversy

20

Non Cancer EndpointRisk = Exposure/ADI

• Exposure = Average Daily Dose– = [(C x IR x EF x ED) / (BW x AT)] x factor

• C = Concentration, e.g., soil = mg/kg• IR = Intake rate, e.g., soil = mg/day• EF = Exposure frequency, days/yr• ED = Exposure duration, years (chronic > 7)• BW = Body weight, 70 kg, child = 16 kg• AT = Averaging time, days

• ADI = Acceptable Daily Intake, RfD

21

Risk

• If ADD/ADI > 1, Risk of Adverse Health Effect

• If ADD/ADI < 1, No Adverse Health Effect Anticipated

22

Cancer Endpoints

• A similar approach is used– Slope Factor is used as the ADI

• = upper 95% CI of dose-response curve• e.g., for ingestion units of mg/kg-day

• Typically an acceptable risk is defined as < 1 x 10-6

– However, 10-4 to 10-5 may be acceptable

23

Time to accumulate 1 in 1,000,000 Risk

Activity

• MV Accident, 1.5 days

• Fall, 6 days

• Drowning, 10 days

• Fire, 13 days

• Firearms, 36 days

• Tornado, 20 months

• Flood, 20 months

• Lightning, 2 years

• Animal bite, 4 years

Occupation

• Mining, 9 hrs

• Firefighting, 11 hrs

• Coal mining, 14 hrs

• Construction, 14 hrs

• Agriculture, 15 hrs

• Transport, 1 day

• Police duty, 1.5 days

• Government, 3.5 days

• Manufacturing, 4.5 days

Adapted from Moeller, 1997

24

Lifestyle activities with1 in 1,000,000 Risk

Eating & Drinking• 0.5 liter wine• 6 # of peanut butter

(aflatoxin)• 180 pints of milk

(aflatoxin)• 200 gallons of

drinking water from Miami, New Orleans

• 90 # of broiled steak

Smoking• 2 cigarettes

Other• Paddling in canoe for 6

minutes• Traveling 10 miles by

bicycle• Traveling 30 miles by

car

Adapted from Moeller, 1997

25

$$ per year of life saved

Program Cost Uncertainty• Childhood measles saves $ low• Lead Phaseout saves $ low• Underground safety rules 52,234 low• Hemodialysis at dialysis ctr. 56,076 low• Coronary artery bypass 67,579 low• Front-seat airbags 108,593 medium• Dioxin effluent control - paper 5,566,386 high• Control of routine PP radiation 164,875,379 high

Adapted from Moeller, 1997

26

“Typical” Risk Perceptions

“Acceptable” if:• Voluntary• Proximate Benefit• Known• Workplace• Natural• Self• Organ Damage• Distant (time, place)

“Unacceptable” if:• Involuntary• No Benefit• Unknown• Residential• Anthropogenic• Children• Cancer• Near

27

ProblemContext

Risks

OptionsActions

Decisions

Evaluation

EngageStakeholders

EPA’s Cardinal Rules of Risk Communication

• Accept & involve public as legitimate partner

• Plan carefully and evaluate your efforts

• Listen to public’s specific concerns

• Be honest, frank, & open• Coordinate & collaborate

w/other credible sources• Meet the media’s needs • Speak clearly and with

compassion

28

10 Key principles of risk assessment, John Graham, HSPS - CRA

• Use the best science for attributable health risk • Acknowledge scientific disagreements• Acknowledge assumptions, & sensitivity of results• Develop central estimates of risk and CI’s + uncertainty• Acceptable risk is policy that requires public involvement• No universally acceptable level of risk exists; context• Health risk decisions require consideration of values

– quality of life, equity, ecological health, choice, economic welfare

• Risk reduction programs should avoid side effects that risk• Programs should consider economic incentives + command c.• Context of risk may be as significant as the magnitude

– voluntary vs. involuntary risk