Introduction to Toxicology Flashcards
Explain key factors that influence toxicity (degree to which toxicant produces harmful effects):
1) Magnitude of exposure (dose)
dose-response relationship
2) Route & site of exposure
inhalation, ingestion, topical, parenteral
3) Duration & frequency of the exposure
acute, subacute, subchronic, chronic
4) Latency of toxic response
Immediate or delayed effect
relate magnitude of exposure to dose-response relationship
The sigmoidal shape of the graph shows:
Causality: whether the toxicant has induced the observed effects
X-axis: log dose concentration Y-axis: Response (% of individuals)
Threshold, no adverse effect level (NOAEL), is very low
Susceptible individuals can show a toxic response to even those very low dose conc (NOAEL)
Resistant individuals will show a toxic response only to very high doses of toxicant
TD50 (the DOSE concentration at which half of the individuals show a toxic response)
The slope of the curve is the rate at which the toxic effects build up in relation to the dose of the toxicant
relate routes/sites of exposure to pharmacokinetics
There are various routes of exposure to the toxicant:
Ingestion (GI tract), inhalation (lungs), topical contact (skin & eyes), parenteral (bites from venomous animals)
Pharmacokinetics also applies to toxicants, in the way that toxicants are less toxic when exposed via the oral route than the intravenous route
This is because, if a toxicant is exposed orally, then it can undergo first-pass metabolism by the gut wall and the liver, this can reduce the toxicity of the toxicant
Larger LD50 for oral > intravenous
explain the impact of duration and/or frequency of exposure on toxicity with examples, being able to classify a scenario according to the duration of exposure
Less than 24 hours exposure: Acute
Exposure between 24 hours – 1 month: Subacute
Exposure between 1 month and 3 months: Subchronic
Exposure over 3 months: Chronic
Toxicity varies, depending on the duration of exposure
Acute exposure = acute toxicity
Chronic exposure = chronic toxicity
Example 1:
Alcohol (drug)
Acute toxicity (24 hours to 1 month): CNS depression, effects depend on BAC
Chronic toxicity (1 month to 3+ months): Alcohol-related liver disease
Example 2:
Benzene (drug):
Acute toxicity (24 hours to 1 month): CNS effects (eg. Headache, dizziness, confusion)
Chronic toxicity (1 month to 3+ months): Bone marrow toxicity
explain latency of toxic response, being able to provide examples
Latency of toxic response means a delay between the initial exposure and the toxic response, which can range from days to years (in utero exposure)
Example 1:
Tri-ortho-cresyl phosphate (TOCP)
Can induce delayed neuropathy (means degradation of axons of the spinal cord and the peripheral neurons)
Muscle weakness and ataxia can appear one week after exposure
TOCP is metabolized by CYP450 (1A2 or 3A4) to form CBDP (which is toxic)
CBDP irreversibly binds to cholinesterases that are essential in degrading acetylcholine, this means that acetylcholine will not break down, and will continue to signal the effector cells to contract, which will lead to muscle weakness over time
Example 2:
Diethylstilbestrol (DES)
Is a synthetic non-steroidal estrogen
Was used previously as a treatment for threatened miscarriages
But instead led to the clear-cell adenocarcinoma of the vagina in the female offspring of the mothers who were treated with DES
But this was a 15+ years delay between the in utero exposure and the toxicity
Example 3:
Thalidomide
Was introduced as a sedative that is non-addictive
To treat morning sickness of pregnant women (studies in mice showed no toxic response)
But then there were thalidomide induced severe birth defects and peripheral neuropathy as a result in children
describe the general mechanisms of toxicity
Lipid peroxidation: change in membrane permeability, that leads to cell damage and death
Production of reactive oxygen species; oxidative stress can impair the function of cells, & cause apoptosis, neuronal death
Depletion of glutathione, which is an endogenous antioxidant, so when it is depleted, will reduce the ability to protect cells from oxidative stress, and therefore cells can die
Formation of DNA/protein adducts: a protein adduct can act as an antigen and can trigger an immune response, whilst DNA adducts can lead to mutagenesis, carcinogenesis, teratogenesis
outline the key advantages of using organ-on-a-chip to assess environmental toxicants compared to conventional models
Useful because human cells will be used – and that will eliminate any inter-species differences
Also useful because it will provide a dynamic 3D environment which will mimic in vivo physiological conditions
describe exposome and its relevance to assessing the impact of the environment on health
Exposome is the complete profile of environmental (non-genetic) exposure of an individual from conception to death
3 factors are measured:
Internal environment: gut microbiota, oxidative stress, metabolic factors
Specific external environment: diet, physical activity, tobacco, alcohol
General external environment: climate, education, social capital
Susceptible individuals are susceptible to a toxicant even at the no adverse effect level (NOAEL)
True or False
True
What is a toxicant?
It is a substance that produces adverse biological effects
Can be a chemical form (drugs, tobacco, cleaning products, pesticides)
Can be a physical form (radioactive materials & radiation)
Can be a biological form (naturally produced by organisms like venoms, toxins)
What is toxicity?
Is the degree to which a toxicant produces harmful effects
route of exposure can be important
acute vs chronic toxicity
target organ toxicity vs systemic toxicity
Bell-shaped curve reflects
The distribution of responses to a given dose of toxicant within a population resembles a typical bell-shaped curve
most individuals respond similarly
small proportions of individuals display either severe response (susceptible) or mild response (resistant) compared to the vast majority of the population
Those few people who have displayed mild reactions to the toxicant are resistant individuals
Those few people who have displayed severe reactions to the toxicant are susceptible individuals
Deviation from dose-response relationships mean…
Deviations from the dose-response relationship mean that there are some individuals within a population who can display exaggerated responses to toxicants (idiosyncratic responses)/ high susceptibility to toxicants
This can be due to genetic factors or hypersensitivity reactions, which involve the immune response
The exaggerated response deviates from the expected response
What is LD50
LD50 (lethal dose 50%) is the amount of toxicant required to kill half of the population, in one dose (mg/kg)
It indicates acute toxicity
A smaller LD50 value means greater toxicity
What reduces toxic effects?
dose fractionation reduces toxic effects
multiple smaller doses are given over a period of time
Dose fractionation in radiotherapy means that a small enough dose is given, which is hopefully sufficient to kill cancer cells, without causing toxic effects on normal healthy cells
exception: carcinogens/mutagens
