**3. Human exposure to EDCs**

change involved in reproductive defects one can note the developmental exposure to vinclo‐ zolin causing an increase in spermatogenic cell apoptosis in the adult rats [23]. This sperma‐ togenic defect was found to be transgenerational at least to F4 generation due to a permanent

• *In vivo* assays providing data on effects clearly linked to endocrine mechanisms

• On a case-by-case basis, *in vivo* assays providing data about single or multiple endocrine mechanisms and effects (OECD, CF levels 3 & 4), combined with other

in combination with *in vivo* ADME information and *in vitro* data

(OECD, CF level 5), but where ED mode of action is suspected

adverse human health effects related to endocrine systems.

human health effects related to endocrine systems.

Many other chemicals have also been implicated in promoting toxicity for multiple genera‐ tions, including BPA [24] or pesticides [25], but in these cases the multigenerational effects involved direct exposures, therefore are not considered transgenerational because they are not transmitted solely through the germ cells. Only effects appearing in the F3 generation are

There are multiple classifications of EDCs, based on their mechanisms of action (on enzymes, transport proteins or receptors), the pathways modulated (e.g., xenoestrogens/antiestrogens,

• *In vitro* assays providing mechanistic data (OECD, CF level 2)

• In special cases, categorization or QSAR approaches may provide the necessary data

• Reliable and good quality evidence from human cases or epidemiological studies

• *In vivo* assays providing data on effects linked to endocrine or other mechanisms

• *In vivo* assays providing data about single or multiple endocrine mechanisms and

• In some cases, read across, chemical categorization and/or QSAR approaches may provide the necessary data in combination with *in vivo* ADME information and *in vitro*

• Good quality epidemiological studies showing associations between exposure and

• QSAR, read-across, chemical categorization, ADME information (OECD, CF level 2) • System biology methods indicating associations between the substance and adverse

**Criteria Available data – according to OECD Conceptual Framework [29,30]**

(OECD, conceptual Framework (CF) level 5)

relevant information

effects (OECD, CF levels 3 & 4)

data

**Table 1.** Classification of EDCs based on Danish criteria

considered to be truly transgenerational [26].

altered DNA methylation of the male germ-line [21].

*Category 1: EDCs*

222 Treatment of Type 2 Diabetes

effects)

• *in vivo data (*mode of action clearly linked to adverse

*Category 2a: Suspected EDCs* • *in vivo data (*mode of action suspected to be linked to

adverse effects)

*in vivo* data

evidence

• *in vitro* mode of action combined with toxicokinetic

*Category 2b: Indicated EDCs*

• *Some in vitro/in silico*

or

Environmental human exposure occurs through a variety of routes and varies widely around the world. Food ingestion represents the major route by which people are exposed to EDCs. For example, diet is thought to account for up to 90% of a person's POPs body burden [31]. Taking into account that these pollutants are accumulated particularly in highly rank preda‐ tors, like fish, in Sweden, consumption of fatty fish from the Baltic Sea is the major source of POPs, but also dairy products and meat contain these pollutants [32]. Also contaminated ground water is a major exposure source to inorganic arsenic in the general adult population in several regions, notably Bangladesh and India [33,34].

Regarding BPA exposure, small amounts of BPA can migrate from polymers to food or water, especially when heated. The human consumption of BPA from epoxy-lined food cans alone is estimated to be about 6.6 µg per person per day [35]. BPA has been found in concentrations of 1–10 ng/ml in serum of pregnant women, in the amniotic fluid of their fetus, and in cord serum taken at birth [36]. Moreover, BPA concentrations up to 100 ng/g were reported in placenta [37], but also in breast adipose tissue, taking into account its lipophilicity.

With the increase in household products containing pollutants and the decrease in the quality of building ventilation, indoor air has become a significant source of EDCs exposure, via inhalation [38]. Published studies [39,40] suggest that contaminated house dust may be the major source of PBBs body burden (up to 82%).

Other routes of exposure include the dermal contact (e.g. parabens or triclosan), via lactation or infants fed formula (especially for phytoestrogens as genistein or BHA). A published study [41] reported that urinary concentrations of genistein and daidzein were about 500-fold higher in infants fed with soy formula compared with those fed cow's milk formula.
