Week 4

Question 1

toxin

Answer 1

a compound of natural origin that exerts notable adverse effects on biological systems

Question 2

toxicant

Answer 2

a synthetic compound that exerts notable adverse effects on biological systems

Question 3

What happens to a toxic substance? (ADME)

Answer 3

1. Absorption:
   - toxicant crosses a biological barrier (e.g., GI tract, respiratory tract, skin)
2. Distribution:
   - toxicant is distributed within the body
3. Metabolism:
   - most substances undergo metabolic conversion, aka biotransformation
   –> mostly in the liver
   –> metabolite may be more toxic than parent compound e.g. methanol
4. Excretion
   - urine, feces, exhaled air
   - or breast milk, placenta to developing fetus

Question 4

Toxicity effects

Answer 4

• mortality (death)
• teratogenicity (ability to cause birth defects)
• carcinogenicity (ability to cause cancer)
• mutagenicity (Ability to cause heritable changes in DNA)
• neurotoxicity (toxic to nerves or nervous system)

Question 5

dimensions of toxicity meaning

Answer 5

factors that determine the likelihood and severity of a toxic effect

Question 6

what are the dimensions of toxicity?

Answer 6

• the toxicant and the “target” organ
• dose
• route of exposure
• timing
• duration
• susceptibility

Question 7

target system and organ toxicity some examples

Answer 7

Central nervous system - lead, mercury, pesticides
Immune - PCBs
Liver - ethanol, acetaminophen
Respiratory - asbestos, ozone
Kidney - cadmium, lead
Skin - UV radiation, arsenic
Reproductive - BPA?, Phthalates?

Question 8

dose

Answer 8

All substances are poisons, the right does differentiates a poison from a remedy
- A non-toxic compound can be toxic at high doses
–> table salt - lethal dose is 3grams in rats
–> vitamin C - lethal dose is 12 grams in rats
- Some compounds such as medications and nutrients can be beneficial at lower doses but toxic at higher doses
–> e.g., acetaminophen

Question 9

Dose-response relationship

Answer 9

Describes how the severity or likelihood of a health effect changes as the dose increases.

• Positive relationship: Higher doses lead to greater effects (e.g., more smoking → higher lung cancer risk).
• Threshold effect: Some substances have a safe level below which no harm occurs
• Nonlinear response: Some substances may have different effects at low vs. high doses (e.g., certain vitamins are beneficial in small amounts but toxic in large doses).

Question 10

Thalidomide

Answer 10

• sedative prescribed to pregnant women for morning sickness in the late 1950s and early 1960s (available in Canada in April 1961)
• removed from the market in most countries by 1962 due to observations of teratogenic malformations
• 40% of affected infants died within 1 year

Question 11

Acute

Answer 11

• short term “bursts” of exposures (hours to days)
• often higher concentrations/doses
• may be followed immediately by symptoms or exacerbation of existing condition

Question 12

chronic

Answer 12

• longer-term periods of exposure (years to lifetime)
• often lower concentrations/doses
• may be associated with onset of new disease (sometimes after long latency period)

Question 13

Measures of toxicity: LD50 - what is it?

Answer 13

Lethal dose 50, the dosage causing death in 50% of exposed animals

Does not provide information on:
- chronic effects
- other (non-mortality) outcomes
- the shape of the dose-relationship
- the presence/absence of a threshold

Question 14

Regulatory toxicology

Answer 14

• closely related to risk assessment
• two categories:
  1. non-carcinogens: threshold based approaches
  2. carcinogens: linear no threshold (LNT) assumption
• this has changed in recent years - now considers the carcinogenic mode of action

Question 15

NOAEL - what is it?

Answer 15

NOAEL - no observed adverse effect level

the highest dose at which the adverse effect is not observed

• NOAELs are like cliffs: once we cross that point, “bad” things start to happen

Question 16

LOAEL - what is it?

Answer 16

LOAEL - lowest observed adverse effect level

the lowest dose at which the adverse effect is observed

Question 17

What is ADI/RfD

Answer 17

ADI - Acceptable daily intake (WHO)
RfD - reference dose (US environmental protection agency)
ADI/RfD = NOAEL / UFs

• estimate of amount of a substance that can be consumed daily over a lifetime without presenting risk to health

Question 18

Threshold-based approaches - RfD or ADI

Answer 18

Acceptable daily intake (ADI) (WHO) or reference dose (RfD) (US environmental protection agency) = NOAEL / UFs
- UFs = uncertainty factors

No effect as long as exposure is below the NOAEL, but once we cross this point, we fall off the cliff
- cliffs are used as analogies for thinking about threshold-based approaches to setting acceptable levels of exposures (RfD or ADI) to chemicals/pollutants

Question 19

PoD

Answer 19

• PoD = point of depature
• the dose at which bad things start to happen
• this is the cliff in toxicology
• we typically use the NOAEL if it is known

Question 20

RfD

Answer 20

RfD - reference dose
RfD = NOAEL / uncertainty factor

Question 21

Non-threshold based approaches - response

Answer 21

if the response or effect begins at zero and increases continuously with a dosage

Question 22

Does hazard = risk?

Answer 22

NO

Question 23

hazard

Answer 23

something capable of causing an adverse effect
- something can be hazardous, but if there is no exposure, there is no risk

Question 24

risk

Answer 24

probability that the hazard will cause an adverse effect under specific exposure condition

Question 25

risk assessment

Answer 25

the process by which hazard, exposure, and risk are determined

Question 26

risk management

Answer 26

the process of weighing policy alternatives and selecting the most appropriate regulatory action based on the results of risk assessment and social, economic, and political concerns

Question 27

Risk assessment steps

Answer 27

Step 1: Problem formulation Step 2: hazard identification (gather information) Step 3: Dose-response assessment (gather info) Step 4: Exposure assessment (gather info) Step 5: Risk characterisation (combine, analyse, make sense of that info)

Question 28

How do we know if something is capable of causing cancer?

Answer 28

Assessments conducted by the International Agency for Research on Cancer (IARC) - an agency within the WHO Categories: Group 1: carcinogenic to humans Group 2A: probably carcinogenic to humans Group 2B: possibly carcinogenic to humans Group 3: not classifiable as to its carcinogenicity to humans Group 4: probably not carcinogenic to humans

Question 29

Gathering information

Answer 29

Hazard identification - ATSDR is often a good place to start Dose-response - IRIS database has dose-response for many chemicals - slope factors for carcinogens, reference doses for non-carcinogens

Question 30

Risk management

Answer 30

Sources: - natural - humanmade --> products, residual, accidents Transport and fate: - media (air, water, land) - bioconcentration Exposure: - human - other species Health effects: - irritant - acute toxic - chronic toxic - cancer - genotoxic Many points where we can intervene to reduce risk

Question 31

Risk perception

Answer 31

influences our individual choices and behaviours, as well as our policy choices

Question 32

technical/quantitative risk

Answer 32

function of hazard, exposure, susceptibility

Question 33

perceived risk

Answer 33

an intuitive judgment about the nature and magnitude of a health risk

Question 34

perception discrepancies

Answer 34

risk communication and risk management efforts are destined to fail unless they are structured as a two way process. 1. Expert 2. Public - each has something valid to contribute.

Question 35

supralinear dose response relationship

Answer 35

small increases in exposure cause disproportionately large effects, but at higher doses, the effect levels off. Example: Air pollution and health risks: - At very low pollution levels, a small increase can cause a large jump in health effects, but as exposure increases the additional ahrm increases more slowly.

Question 36

Describe the use of uncertainty factors in establishing acceptable doses in humans.

Answer 36

this approach sets the acceptable intake at a fraction of the NOAEL to provide a "margin of safety"

Question 37

How does traditional risk assessment differ between carcinogens and non-carcinogens?

Answer 37

non carcinogens are threshold based approaches carcinogens are linear no threshold assumptions

Question 38

Linear dose response relationship

Answer 38

if dose and response increases/decreases at the same pace. - more dose = more response - less dose = less response

Question 39

What is threshold?

Answer 39

max amount of something that has no effect, it is amount where you can be exposed to the toxin and be safe