by Dr. Wade V. Welshons

Endocrine disruption is one of a number of mechanisms that can lead to toxic endpoints. However, when present, endocrine disruption is usually the abnormal or adverse endpoint which occurs at the lowest exposure, in part because it can act through receptor mechanisms like the dioxins. Therefore endocrine disruption will generally be the most important mechanism in assessing risk, and the current "safe" levels for POPs such as DDT, based on nonspecific toxicity endpoints, are thousands of fold higher than the levels at which fetal endocrine disruption has already been described. The nature of the endocrine disruption by the POPs strongly supports POPs treaty goals.

1. POPs as endocrine disruptors, and what endocrine disruption is.

2. Endocrine disruption by DDT (one of the 12 POPs chemicals) at the current "acceptable daily intake" (ADI) exposure level of 20 ppb per day.

3. Why the fetal development and childhood development periods are more sensitive to endocrine developmental disruption than is the adult.

4. How endocrine disruption at very low exposures is accurately predictable.

5. Studies of DDT and PCB exposures and human developmental effects in Mexico and the US, and evidence of developmental disruptive effects at levels of frequent current exposure.

6. Minimizing new or additional fetal and childhood exposures to the POPs is a priority to address their endocrine and developmental disruption.

1. List of POPs - All of the POPs are endocrine disruptors directly or indirectly. Fully half belong to the group of estrogenic endocrine disruptors, the kind I study and will use to describe what endocrine disruption is. Including their products of incomplete combustion (PICs) all POPs are developmental disruptors as well as endocrine disruptors.

2. Endocrine Organs in the body - Hormones are normal chemical messengers; any disruption of hormone signaling creates abnormal signaling in the adult and creates abnormal development in the fetus; endocrine disruption occurs by several different kinds of mechanisms - one for thyroid disrupting PCBs, second for estrogen disruptors which are the most widely occurring based on what have currently been described.

Disruption of endocrine system, disruption of normal function with chemical E or antiE; reproduction impaired by either too much (addition by estrogenic EDC) or too little (inhibition by antiestrogenic EDC); in addition for estrogens increase is a risk factor for hormone-dependent cancers particularly breast cancer; there is a cost to the organism to use estrogens in signaling.

3. ER Model - all estrogens and all environmental estrogens act through intracellular receptor model; entry into cell required to be an EE, and POPs persistence associated with lipid partitioning (Rodan) which also confers ability to cross membrane, so all POPs have this feature required by the EE EDCs; phenolic hydroxyls in nearly all chemical and natural estrogens, and such aromatic rings widely used in synthetic organic chemistry, accidentally coincides with structures that are estrogens.

4. Wide Dose-Response, toxicity vs hormonal activities - receptor mechanism can confer activity at very low exposures; toxicity of dioxins, the most toxic manmade chemicals, and the most toxic of the POPs, is mediated by the same class of intracellular receptor that mediates endocrine disruption by environmental estrogens; toxicity of POPs has been determined at the higher ranges, and endocrine disrupting doses not tested.

Estrogenic effects only seen in estrogen receptor + targets, only the high-dose, non-estrogenic toxicity visible in non-target tissues; estrogen effects when present occur at lower dose that other tox, perhaps 100's-fold and lower; may be greater endocrine disrupting potential.

5. DDT/DES Urine Marking - Effect of one of the POPs, DDT, on behavior at very low fetal exposures, approximately 20 ug/kg; DDT estrogenic like DES and methoxychlor, but at different (higher) doses.

6. Adult-Newborn-Fetus - why the fetus is an important target; adult most tested, but fetus most sensitive and effects may be on development of organ systems and may be permanent.

7. Oswego Newborn and Infant Development Project Introduction - Human POPs exposures are complex and mixed; 2/3 of main pollutants listed for Lake Ontario in US are POPs.

8. Mexico data - increased DDE in body fat associated with reduced lactation time; proposed estrogenic (or other hormonal activity) stops lactation, as does estrogen; developing country lactation important for infant viability.

9. Jacobson Table - IQ, Freedom from Distractibility, and others impaired by PCB exposure; significance associations only with prenatal exposure, even though breast feeding can transfer more PCBs.

10. POPS Structures - Structures of POPs favor endocrine disruptors - phenolic groups and hydrophobicity/persistence.