Week 4 Flashcards
toxin
a compound of natural origin that exerts notable adverse effects on biological systems
toxicant
a synthetic compound that exerts notable adverse effects on biological systems
What happens to a toxic substance? (ADME)
- Absorption:
- toxicant crosses a biological barrier (e.g., GI tract, respiratory tract, skin) - Distribution:
- toxicant is distributed within the body - Metabolism:
- most substances undergo metabolic conversion, aka biotransformation
–> mostly in the liver
–> metabolite may be more toxic than parent compound e.g. methanol - Excretion
- urine, feces, exhaled air
- or breast milk, placenta to developing fetus
Toxicity effects
- 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)
dimensions of toxicity meaning
factors that determine the likelihood and severity of a toxic effect
what are the dimensions of toxicity?
- the toxicant and the “target” organ
- dose
- route of exposure
- timing
- duration
- susceptibility
target system and organ toxicity some examples
Central nervous system - lead, mercury, pesticides
Immune - PCBs
Liver - ethanol, acetaminophen
Respiratory - asbestos, ozone
Kidney - cadmium, lead
Skin - UV radiation, arsenic
Reproductive - BPA?, Phthalates?
dose
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
Dose-response relationship
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).
Thalidomide
- 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
Acute
- short term “bursts” of exposures (hours to days)
- often higher concentrations/doses
- may be followed immediately by symptoms or exacerbation of existing condition
chronic
- 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)
Measures of toxicity: LD50 - what is it?
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
Regulatory toxicology
- 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
NOAEL - what is it?
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
LOAEL - what is it?
LOAEL - lowest observed adverse effect level
the lowest dose at which the adverse effect is observed
What is ADI/RfD
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
Threshold-based approaches - RfD or ADI
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
PoD
- 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
RfD
RfD - reference dose
RfD = NOAEL / uncertainty factor
Non-threshold based approaches - response
if the response or effect begins at zero and increases continuously with a dosage
Does hazard = risk?
NO
hazard
something capable of causing an adverse effect
- something can be hazardous, but if there is no exposure, there is no risk
risk
probability that the hazard will cause an adverse effect under specific exposure condition
risk assessment
the process by which hazard, exposure, and risk are determined
risk management
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
Risk assessment steps
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)
How do we know if something is capable of causing cancer?
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
Gathering information
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
Risk management
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
Risk perception
influences our individual choices and behaviours, as well as our policy choices
technical/quantitative risk
function of hazard, exposure, susceptibility
perceived risk
an intuitive judgment about the nature and magnitude of a health risk
perception discrepancies
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.
supralinear dose response relationship
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.
Describe the use of uncertainty factors in establishing acceptable doses in humans.
this approach sets the acceptable intake at a fraction of the NOAEL to provide a “margin of safety”
How does traditional risk assessment differ between carcinogens and non-carcinogens?
non carcinogens are threshold based approaches
carcinogens are linear no threshold assumptions
Linear dose response relationship
if dose and response increases/decreases at the same pace.
- more dose = more response
- less dose = less response
What is threshold?
max amount of something that has no effect, it is amount where you can be exposed to the toxin and be safe
