Figure 4.

NOAEL, LOAEL, and calculation of a safe reference dose. A, In traditional toxicology testing, high doses are tested to obtain the maximum tolerated dose (MTD), the LOAEL, and the NOAEL. Several safety factors are then applied to derive the reference dose, i.e. the dose at which exposures are presumed safe. This reference dose is rarely tested directly. Yet when chemicals or hormones produce NMDRCs, adverse effects may be observed at or below the reference dose. Here, the doses that would be tested are shown by a dotted line, and the calculated safe dose is indicated by a thick solid line. The actual response, an inverted U-shaped NMDRC, is shown by a thin solid line. B, Experimental data indicate that EDCs and hormones do not have NOAELs or threshold doses, and therefore no dose can ever be considered safe. This is because an exogenous hormone (or EDC) could have a linear response in the tested range (dotted line), but because endogenous hormones are present (thin solid line), the effects of the exogenous hormone are always observed in the context of a hormone-containing system.