Toxicology - Risk assessment

What is a risk assessment?

The process by which hazard, exposure and risk are determined.

• Risk = hazard x exposure

What are different routes of exposure?

• gastrointestinal tract (oral)

• lungs (inhalation)

• skin (dermal)

• injections (for medicines)

How do you assess duration and frequency of exposure?

Acute —> <24 hours, single dose

Sub-acute —> one month or less, repeated exposure

Sub-chronic —> 1-3 months, repeated exposure

Chronic —> >3 months, repeated exposure

What is an example of acute exposure?

• Methyl isocyanate

• arsenic —> skin cancer

what are examples of acute vs chronic toxicity?

What does EDI stand for?

EDI = estimated daily intake

• assessed using probability (concentration x consumption)

How do you assess non-genotoxic compounds?

• NOAEL (no observable adverse effect level)

• LOAEL (lowest observed adverse effect level)

• Benchmark dose approach

• ADI & TDI

Poor quality data

What are advantages & disadvantages of the benchmark dose approach?

Advantages:

• Use all data

• independent of choice of exposure

Disadvantages:

• effect levels, no info on non-effect levels

• low effect levels are difficult to quantify

How do you characterize a risk?

Margin of safety (MOS) should be:

• (ADI/EDI) >/= 1

• (NOAEL or BMDL/EDI) >/= 100

What is the margin of exposure for substances that are neither genotoxic nor carcinogenic?

• the uncertainty of effects does not allow an established ADI or TDI

  • min. MOE is 100 or larger

    • below 100 is public health concern

What is an example of a non-genotoxic chemical?

• vomitoxin (DON)

  • trichothecene from fusarium spp on wheat —> immunotoxicity, growth retardation

• cyclamate

  • ADI cannot be unchanged

  • MPL will be reduced

How do you conduct a risk assessment for genotoxic carcinogenic compounds?

Avoidable contaminants:

• zero tolerance —> compound cannot be used

Unavoidable contaminants:

• ALARA —> as low as reasonably achievable

• VSD (virtual safe dose) —> define dose with acceptable cancer risk

• MOE (margin of exposure)

What are examples of genotoxic carcinogenic compounds?

• acrylamide

• estragole

Is a quantitative risk assessment for genotoxic carcinogens accepted?

No, it is not accepted

• low dose cancer risk extrapolation —> differences by different models

• linear extrapolation —> unrealistic (too many assumptions)

• outcomes give false sense of accuracy

• chances of misuse and misinterpretation of outcome

• too much considered as true by consumers, politicians and managers

• species differences are not taken into account

How do you find and interpret the MOE for genotoxic carcinogenic compounds?

MOE = BMDL/EDI

• MOE used by risk managers to set priorities

• MOE > 10000 low priority for risk management

Why is the MOE for genotoxic compounds 10000?

The 100 fold factor (from not genotoxic carcinogens) is multiplied by an additional factor of 10 to account for differences in human cell ability to repair DNA. To account for any other uncertainties an additional factor of 10 is added.

What is risk management?

An action taken by risk managers based on toxicological risk assessment, social, economical and political aspects.