9. Hazard characterization

Hazard characterization

• Actions and interactions of the toxic compound within the organism and described the processes at organ, tissue, cellular and molecular levels

• “effects of compounds”; dose response relations

• Based on in vitro and or in vivo data

ADI vs TDI

• ADI = For chemicals where we have a choice if we put it on the market

• TDI = Cannot be avoided, e.g. PFAS

How do we derive an ADI/TDI

• Expose cells/organisms to increasing concentration of a compound

• Select endpoints to measure

• Establish the best possible test (or follow the guidelines)

• Data analysis and reporting

NOAEL approach

• NOAEL: No-Observed-Adverse-Effect Level

• t-test/ANOVA: can measure which concentration gives a significantly different response from the control

• LOAEL: lowest concentration that differs significantly (Lowest observed effect adverse level)

• NOAEL: Highest concentration that does not differ (No-Observed Adverse Effect Level)

Disadvantages of NOAEL approach

If there are less data points, LOAEL will be much lower compared to if there are more data points.

• Therefore dependent on experimental design

  • If a company wants to use higher concentrations of a dangerous chemical they can do a bad study with little data points giving them a higher NOAEL - Gives bias

• Hence NOAEL - NOAEL differ across studies

Regression analysis

• Regression analysis: integrate the dose-response curve using all data and calculate toxicity compared to the control

• Here gaps between data points are not a problem like in NOAEL because of the regression line

• EC10 = concentration with 10% effect

• EC50 = concentration with 50% effect

Advantages and disadvantages regression analysis

Advantages:

• All data used

• Independent on experimental design

• Estimation of extent on effect

Disadvantages:

• “no effect” concentrations not known

Benchmark dose modelling

In this approach the dose response curve is modelled and the dose at a specified critical response effect (benchmark response or BMR) is observed and calculated.

• Benchmark Response (BMR): a 1 to 10 percent response above background level

• BMD: Bench mark dose causing the BMR

• When analyzing a dose-response with the BMD method the variation in responses is taken into account.

• This results in the benchmark dose lower confidence limit (BMDL)

• This is the dose at which the effect is smaller than the BMR (with defined confidence)

Advantages and disadvantages of benchmark dose approach

Advantage:

• If a bad study is done, then the BMDL is much lower, which companies don’t want therefore they will do good studies so that they can use more of their chemicals

How are NOAEL BMDL corrected for uncertainty?