Route and Site of Exposure

Hazardous chemical compounds can gain access to the body via the major routes of ingestion (gastrointestinal tract), inhalation (lungs), and skin contact (topical, percutaneous, or dermal exposure). Toxic compounds can produce the greatest and most rapid effect when access is directly into the bloodstream through an intravenous route. In addition, the route of exposure can influence the toxicity of the chemical compounds. For example, a compound that is detoxified in the liver would be less toxic when ingested than through inhalation.

To exert any toxic effect on testicular tissue or sperm cells, the compound or its metabolite would have to breach the blood–testis barrier. In women, the uterus, ovary, and follicles can be exposed to compounds ingested, inhaled, or absorbed through the skin. However, the oocyte may have some protection by the surrounding granulosa cells providing a barrier similar to the blood–testis barrier.

Occupational exposure to toxic agents results mostly from breathing contaminated air and/or direct and prolonged contact of the skin with the substance, whereas accidental poisoning occurs most often by ingestion. Factors that can increase toxic effects by any route of exposure are the concentration of the compound, and the duration and rate of exposure. One principle of toxicology is that any compound can exert a toxic effect. The Swiss physician and scientist Paracelsus (1493–1541), is famed for the phrase: ‘What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison’ – or simply put – ‘it is the dose that makes the poison’.

Compounds regarded as highly toxic will exert a toxic effect at very low concentrations. An example is botulinum toxin, which is produced by Clostridium botulinum bacteria and can be lethal in the ng/kg range. Other well‐known toxic compounds such as arsenic or strychnine can be lethal in the mg/kg range.

The exposure to potentially toxic substances can be acute, subacute, subchronic, and chronic. Acute exposure is exposure to a hazardous chemical or agent for fewer than 24 hours. Repeated exposure can be subacute, subchronic, and chronic. Subacute exposure refers to repeated exposure to a hazardous chemical or agent for 1 month or less, subchronic for 1–3 months, and chronic for more than 3 months.

Mechanism of Toxicity

The degree of toxicity depends on the route of exposure, concentration of the hazardous chemical or agent, and duration of exposure. Cellular damage occurs when the toxin/toxicant results in perturbations in cell function and/or structure beyond any repair capacity. Some chemicals can alter the biological microenvironment (Figure 17.1). Heavy metals like cadmium can alter actin filament function, thus disrupting cell structure and tight junctions between cells. A number of agents such as strong acids and bases, nicotine, aminoglycosides, ethylene oxide, heavy‐metal ions, hydrogen cyanide, and carbon monoxide are directly toxic, whereas the toxicity of other agents can be due to the action of their metabolites. Many chemicals can be genotoxic or mutagenic, damaging DNA, while others can interfere with cellular functions such as metabolism, cell division, and cell membrane integrity. Some chemicals can activate protein target molecules, mimicking endogenous ligands, which can interfere with normal cellular signalling activity. An important class of such chemicals are the endocrine‐disrupting chemicals, which interfere with the production, binding, or action of physiological hormones.

Heavy Metals

Mercury, cadmium, and lead are toxic to humans. There have been associations between welding and reduced sperm motility and concentration.

Lead exposure (primarily from paint) has been concomitant with negative effects on male fertility, with poor sperm motility, lower sperm concentration, and abnormal morphology. Lead exposure has also been implicated as a factor for poor fertilization rates in in vitro fertilization (IVF) (Benoff et al. 2003). Lead may affect pituitary function therefore disrupting the hypothalamic–pituitary gonadal axis, leading to hypogonadism. Lead is also known to affect fetal development with long‐term effects on cognitive abilities (Schnaas et al. 2006).

Cadmium (a known carcinogen) exposure, usually from food sources such as shellfish, even at low levels has been implicated in poor sperm parameters and altered levels of reproductive hormones, increasing time to pregnancy. Cadmium is associated with human prostate cancer and in animal studies has shown to induce benign Leydig cell tumours, likely due to testicular necrosis and atrophy resulting in overstimulation from luteinizing hormones (LH) (Waalkes 2003). Cadmium’s effect on Sertoli cell tight junctions may be due to its actions on the actin filaments associated with these junctions, which results in loss of tight junctional barriers leading to oedema, increased fluid pressure, ischaemia, and tissue necrosis (Li and Heindel 1998). Cadmium‐induced capillary toxicity can also affect the pampiniform plexus leading to testicular necrosis and ischaemia.

Mercury exposure can result in abnormal sperm morphology and poor motility, and in women is associated with a doubled risk of miscarriage (Cordier et al. 1991). Methylmercury (exposure typically through a fish‐rich diet) can cross the placenta and concentrates 5–7‐fold more in the fetal brain than in the mother’s blood. High concentration causes widespread damage to the fetal brain, although for low levels of methylmercury exposure the results are inconsistent (Counter and Buchanan 2004).

Endocrine‐Disrupting Chemicals

Endocrine‐disrupting chemicals can be described as chemicals that can interfere with the endocrine systems. The chemicals usually mimic endogenous hormones either structurally or functionally and can cause a range of disorders: cancerous tumours, metabolism disruption, neurological function disruption, developmental disorders, and congenital defects. Endocrine disruptors affect normal endocrine function and some have severe impacts on the hypothalamic–pituitary gonadal axis, causing infertility. The route of exposure is variable and includes: industrial products, personal care goods, water, air, and food. Endocrine disruptors can also accumulate in the food chain, and although some substances such as DDT and PCBs were banned more than 30 years ago, they are still detected in human bodily fluids due to the lack of biodegradability of these chemicals and their lipophilicity. Chronic exposure to endocrine‐disrupting chemicals can occur via inhalation and skin contact. However, the primary source of these chemicals is through food and water. The use of xenoestrogens in the food industry has resulted in amplified levels of sex steroid hormones in processed foods (milk, meat).

Bisphenol A (BPA) is a synthetic compound that is commonly used to make plastics and resins. It has been shown to leach from plastics under normal use. BPA is classed as a xenoestrogen (oestrogen mimicker)/endocrine disrupter. It has never been used as a drug, however; BPA is structurally similar to diethylstilboestrol which was used as a synthetic oestrogen in women and animals until its ban in the 1970s due to its carcinogenicity. When BPA was tested for use as a synthetic oestrogen it was found to be 1000–2000‐fold less effective than oestradiol (other studies have shown up to 100 000‐ fold lowered affinity for oestrogen receptors) but the oestrogen mimicking effects of BPA are due to the similarity of the phenol groups in oestradiol and BPA. In high concentrations BPA binds to the androgen receptor and acts as an antagonist (Kwon et al. 2007; Vandenberg et al. 2007; Vogel, 2009). Unconjugated BPA has repeatedly been measured in human serum, plasma, placenta, amniotic fluid, and breast milk (low ng/mL range) and BPA conjugates are detected in human urine in over 90% of multiple populations in different continents (low ng/mL range) (Vandenberg et al. 2007). BPA has been implicated in many human health issues including cardiovascular disease, diabetes, liver enzyme abnormalities, and obesity. The more significant effects are usually seen when exposed from fetal stage to early childhood leading to secondary sexual development changes, immune disorders, and neurobehavioral changes; therefore pregnant women, infants, and young children are the most at risk groups (Erler and Novak 2010). Other studies have also shown BPA exposure with meiotic spindle disruption in oocytes, reduced ovarian response and poor IVF outcomes, reduced fertilization and poor embryo quality, poor implantation rates, increased risk of miscarriage, premature birth, altered sex hormone concentrations, altered thyroid hormone concentration, and poor sperm quality (Rochester 2013).

PCBs were primarily used as dielectric or coolant fluids in electronic equipment. In the 1960s PCBs were shown to accumulate in the environment, acting as a persistent organic pollutant, which may be a major source for human exposure. PCBs have been classified as definite human carcinogens, and are known endocrine disruptors. PCBs can produce either oestrogenic or antioestrogenic effects, which can lead to developmental issues for both male and females, poor sexual development, skeletal problems, mental development issues. In males, PCBs negatively correlate with testosterone. In adults, high levels of PCBs have shown to reduce levels of thyroid hormones, which can impact on many other physiological process in humans (growth, metabolism, temperature, and heart rate) (Hagmar et al. 2001; Schell et al. 2014).

Organic Solvents

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