Principles of Toxicology 3 Flashcards
define HAZARD:
is the intrinsic potential of a chemical to cause harm
- it is a qualitative expression
what is toxicity equal to ?
= f(chemistry) x f(biology) x exposure
chemistry= structure
biology- of exposed organism
the extent of exposure
define: RISK
is the probability that harm will occur under defined conditions
- often able to quantify risk and manage it
what is risk equal to ?
= hazard x exposure
what is the purpose of risk assessments ?
reduces the probability of harm which will occur in the environment
what is an example used to differentiate between hazard and risk ?
botulinus toxin
- it is one of the most potent toxins known so the hazard for it is extremely high however very few people have died from it in the UK because the exposure to it is very unlikely
therefore risk to human health is low
why does the assessment of hazard change with time ?
due to more information about the toxicology of a chemical becoming available
why does the perception of hazards change with time ?
until the advent of immunization and antibacterial chemotherapy, death from bacteria was a much greater risk to human compared to exposure to toxicants/toxins
whereas now
we have to be aware of the safety of chemicals and physical agents instead of survival
nowadays we take for granted the advances in science and technology which contribute to survival
define:RISK ASSESSMENT
the use of scientific data and a clear set of assumptions to define the likely health effects of exposure of individuals or populations to hazardous materials and situations
why is the assessment of toxicology risk difficult ?
there are many different variables to consider which contribute to the outcome
often very little information to determine these variables
what is the threshold of pathological condition ?
it is the point at which the signs and symptoms of toxicity become apparent
what is one of the major problems to determine whether chemical are safe?
major challenge to develop methods to determine their safety
when a new chemical is produced what toxicology is known ?
nothing there is complete uncertainty about nature and possible adverse effects
all that is known is that as the exposure increases the probability of toxicity will increase but the nature and incidence of adverse effects are not known
what is known about a new chemical ?
its properties are known such as hydrophobicity and acidity so therefore predictions about its toxicity can be made
what is in silico/in vitro data ?
in silico methods= predictions based on chemical structure
in vitro tests (ames test) and animal studies are often the starting points for hazard recognition
why should in silico/in vitro studies be carried out to determine toxicology ?
to determine target organ
the exposure-toxic response relationship = define the incidence and severity of adverse effects
what is the amnes test ?
used to determine whether a chemical is likely to be a mutagen or carcinogen
what is level is determined from in silico/in vitro tests ?
an estimate for the no observed adverse effect level (NOAEL)
what strategy does the estimate of NOAEL lead to ?
it leads to the RISK MINIMIZATION - this should prevent the adverse effects in man
- a means of illustrating this is by clinical trials
what is the NOAEL used to calculate ?
starting dose for phase 1 clinical trials and a dose that would be safe to take as a daily intake as a food additive
how is the NOAEL calculated ?
NOAEL for the most sensitive species and the primary toxic effect is divided by a safety factor
what is the safety factor normally and why ?
normally 100
based on the assumption that man is 10 times MORE sensitive than the most sensitive animal species and that clearance is 10x SLOWER than in animals
what does risk minimization aim to determine and also what does this mean for phase 1 clinical trials ?
aims to determine an appropraite exposure level of a chemical based on animal study data
it means that in phase 1 clinical trials there is a high degree of confidence that the chemical will not cause toxic effects
animal data is not sufficient for risk assessments so what happens next ?
need a risk assessment produced from observations in man
therefore to minimize adverse effects quantitative data needs to be obtained from man
how is quantitive data about toxicity obtained from man ?
clinical trials
epidemiological studies - pattern of health of patients treated with the drug
accidental exposure- often chemicals other than drugs
what are the different stages for risk assessment of a potential drug ?
hazard identification- first step- info from in silico, in vitro and animal studies
exposure-response relationships- extrapolation from animal studies and human studies
exposure assessment- estimated exposures, routes of entry an characteristics of population
risk determination and deciding on acceptable risk - risk vs benefits
management of risk - sold over the counter, prescription only and saftey within work place
why are toxicologists often interested in the metabolisation speeds of drugs ?
because fast metabolism are often less of a risk if it is the parent metabolite that is more toxic but is more of a risk if the metabolite of the parent drug is more toxic
what is the golden rule in risk assessment ?
for the government to enable a drug to be approved it must impose no greater risk on those individuals exposed to it as those authorizing it would tolerate
what happens when the NOAEL is difficult to determine ?
a benchmark exposure is determined for a specified effect
- a more vigourous saefty factor is applied- often increased to 1000
what is TTC?
threshold of toxicological concern
what is the purpose of TTC?
it is impossible to determine the toxicity of all different chemcials
therefore TTC enables an alternative approach based on in silico predictions of numerous toxicological end points like mutagenicity and level of exposure to determine a TTC of groups of chemicals
what is an example process of TTC ?
TTC for organophosphate pesticides is 18 micrograms per kg of body weight per day
if intake is less than 18 then its considered not to impose risk but if it is greater a risk assessment is needed based on in vitro and in vivo toxicity tests
what should the process of risk evaluation estimate ?
the size of the exposed pop the intensity of exposure the frequency of exposure the duration of exposure potential routes of entry
which groups are likely to be susceptible to toxic effects ?
the young and elderly
recognised that actually the sensitivity to toxic chemicals is genetically determined
why can safety no be absolutely determined?
because it is not guaranteed that a chemical will not cause any harm
what influences safety ?
economics
politics
public opinion
what is the precautionary principle?
its an approach to risk management in which its states that is it better to be safe than sorry
anticipation of dangers and therefore trying to minimise them occuring
what is REACH?
registration evaluation authorisation chemicals this is a regulatory process for the assessment of the safety of chemicals which is determined by the EU
what are the key objectives of REACH?
improve the protection of human health and environment
provide a more transparent system for risk assessment and the control of chemicals
promote non animal testing
what are the requirements of reach ?
since 2008 chemicals manufactured in th EU or imported in quantities starting at a tonne have to be registered
- this means there must be adequate information to provide to the EU chemical agency to assess its safety and prove its undergone a responsible risk assessment
if there is a risk about the substance the agency has to provide authorisation for it to made, imported and distrubuted in the EU
