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Toxicology Reflections


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Trihalomethanes in Drinking Water

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About Trihalomethanes

Trihalomethanes are compounds consisting of a carbon atom bound to a hydrogen atom and three halogen atoms (i.e. like methane, but with three of the hydrogen atoms replaced with halogens such as fluorine, chlorine, and/or bromine).  The halogen atoms can be of the same type or in different combinations.  Chloroform is a well-known example of a trihalomethane that has many industrial and chemical applications; these compounds are not unique to drinking water and exposure to trihalomethanes can occur due to environmental contamination as well as through drinking water.

Trihalomethanes in Drinking Water

Chlorination and filtration of water supplies if often cited as one of the greatest public health achievements of the 20th century, greatly reducing the incidence of diseases such as cholera, dysentery, and typhoid (Calderon, 2000) where implemented.  However, it was discovered in the 1970s that chlorine could react with naturally-occurring organic matter in the water to form trihalomethanes (THMs), especially chloroform.

THMs are sometimes also referred to as disinfection by-products, or DBPs.  While THMs appear to be the first DBPs recognized, we are now aware of over 600 compounds that appear in drinking water as a result of a variety of disinfection processes (Richardson, 2012).  However, only a few DBPs are regulated, and this discussion will be limited primarily to THMs formed as a result of chlorination.

There are four trihalomethanes that have historically been of concern in drinking water, which are sometimes grouped under the heading total trihalomethanes or TTHMs:

  • Chloroform (CHCl3)
  • Bromodichloromethane (CHCl2Br)
  • Dibromochloromethane ( CHClBr2)
  • Bromoform – (CHBr3)

Of these, it is chloroform that forms the basis for the minimum acceptable concentration of THMs in Canada (with respect to drinking water standards), because it the compound for which the most data on toxicological effects is available.  The drinking water standard is based on the cumulative dose of all four THMs.  Canada also has a separate standard for bromodichloromethane (even though it is also included within the trihalomethane guideline).  The guidelines are primarily based on evidence from animal studies that identify chloroform as a potential carcinogen.  Human studies have also suggested links to cancer, and at high levels reproductive effects.  It has been suggested that trihalomethanes that contain bromine are more toxic than chloroform, and bromodichloromethane has been identified as a carcinogen in rodent studies (it is thought to be the most potent carcinogen of the four trihalomethanes being considered, at least in rodents)(Health Canada, 2006).  Other guidelines are in effect elsewhere, as will be discussed in future reflections along with the rationale for these guidelines.

Other topics for reflection will included balancing the concern over trihalomethanes against the benefits of disinfecting water supplies, the importance of exposure routes, considering the risk of trihalomethanes relative to the risks of byproducts from alternate disinfection methods and relative to the hundereds of other disinfection by products.

 

References cited:

Calderon, R. L. (2000). The epidemiology of chemical contaminants of drinking water. Food and Chemical Toxicology38, Supplement 1(0), S13–S20.

Government of Canada, H. C. (2006, May 2). Guidelines for Canadian Drinking Water Quality: Guideline Technical Document: Trihalomethanes – Health Canada. publication. Retrieved September 10, 2013, from http://www.hc-sc.gc.ca/ewh-semt/pubs/water-eau/trihalomethanes/index-eng.php

Richardson, S. D., & Postigo, C. (2012). Drinking water disinfection by-products. In Emerging Organic Contaminants and Human Health (pp. 93–137). Springer. Retrieved from http://link.springer.com/chapter/10.1007/698_2011_125

 

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Importance of Soil Background Concentrations

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Decisions on the remediation of metal contaminated soils are based on risk estimates derived from soil guideline values. Soil guideline values for metals are most commonly based on toxicological reference values. However guideline values are not only a reflection of scientific understanding but also reflect political decisions and legislative requirements, implemented by the regulator.

The United Kingdom is one such example of how changes to legislation of influenced the need to understand background soil concentrations. Part 2A of the contaminated land stator Guidance was issued by Department of Environment, Food and Rural Affairs in April 2012 (Defra, 2011). This guidance outlined changes to how contaminated land would be considered in the United Kingdom. Under this new guideline the term “normal” was introduced to the regulatory system with the requirements to remediate soils to normal levels.

Normal background concentration of soil contaminants not only includes geological and natural variation in soil element concentration but that of historical contamination and “normal” concentration of different elements found in soils of different environments (urban vs. rural). This series of post will be considering the important of determining soil background concentration and the different approaches which can be used to derive background concentration of soil contaminates in the environment.

Defra, 2011. Draft Contaminated Land Statutory Guidance


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The Controversy of Caffeine

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There is a lot of debate around whether caffeine is “safe” or not.  There are old wives’ tales regarding coffee stunting children’s growth and leeching calcium from bones.  But does it?  Caffeine is often used as a stimulant to help users stay mentally and physically alert.  What sorts of benefits does it really give?  Nearly all of us have felt our hearts race after an energy drink or an extra strong cup of coffee.  Could caffeine be to blame for heart disease and high blood pressure?  Does it cause cancer?  Is it addictive and can you experience withdrawal?  Some tout it as a cure for hyper activity and/or ADHD.  Since it crosses the blood-brain barrier how much is “safe” for adults?  Could it be a leading cause of infertility? What are its effects after crossing the placental barrier?  Is it “safe” for children? Is caffeine really “good” or “bad”?  For such a ubiquitous substance I feel I have a severe lack of knowledge on the subject.  With the following posts I hope to educate myself and readers on one of my favourite substances.  By discussing findings in the literature hopefully some of the questions asked above can be answered.

So where does dietary caffeine come from?  Caffeine (1,3,7-trimethylxanthine) is a nitrogenous organic compound produced by plants.  It is found in the seeds, fruit and leaves of plants such as coffee (beans), cocoa (beans), tea (leaves), and kola (nut).  When these plants are ingested we inevitably intake some caffeine.  Caffeine compounds are also added to consumables such as soft drinks, chocolate, energy drinks, and medications (cold, headache and pain remedies, over the counter stimulants and other drug products)1,2.  According to Health Canada Canadian adults get approximately 60%, 30% and 10% of their caffeine from coffee, tea and cola beverages/chocolate/medicines respectively.  Children (1-5yrs) get approximately 55%, 30% and 14% from cola drinks, tea and chocolate respectively.

Health Canada1 recommends healthy adults keep caffeine intake to 400 mg/d (about 3 8oz cups of brewed coffee), 300 mg/d for women of childbearing age and 2.5mg/kg for children.  That is approximately 45mg for children 4-6 years old, 62.5mg for children 7-9 and 85 mg for children 10-12.  These ranges encompass about 1-2 12oz cans of cola per day (considering the health effects of caffeine only).  To accurately calculate your daily caffeine intake visit Health Canada’s website where they provide a detailed guide on amounts of caffeine found in various foods.

For some additional information on caffeine consumption visit these websites (accessed September 2013).

Graphs on international coffee consumption

http://www.unctad.info/en/Infocomm/Beverages/Coffee-French-version-only/Market/

Interesting graphs on Canadian beverage consumption – soft drink industry website

http://www.agr.gc.ca/eng/industry-markets-and-trade/statistics-and-market-information/by-product-sector/processed-food-and-beverages/the-canadian-soft-drink-industry/?id=1172167862291

Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A & Feeley M (2003) Effects of caffeine on human health.  Toxicological Evaluation Section, Chemical Health Hazard Assessment Division, Bureau of Chemical Safety, Food Directorate, Health Canada.  Food Additive and Contaminants 20,1-30.

Health Canada (2013)  Caffeine: It’s your health.  http://www.hc-sc.gc.ca/hl-vs/iyh-vsv/food-aliment/caffeine-eng.php (accessed September 2013).


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2,4-D: Bad for Me?

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Used widely for domestic and agricultural purposes, 2,4-dichlorophenoxyacetic acid (2,4-D) has been well known commercial herbicide since the 1940s.  According to Statistics Canada (2006), almost half of Canadian farms reported use of herbicides, including 2,4-D, on over 24 million hectares of land in addition to its domestic use for aesthetic purposes in yards and gardens.  Used to control broadleaf plants, 2,4-D is found commercially in three main forms: alkali salts, amine salts and esters (HC 1993).  As a herbicide, 2,4-D is applied directly for weed control but has the potential to enter the environment through many pathways including accidental spills, excessive application, runoff and aerial drift (HC 1993).

For humans, potential pathways to 2,4-D exposure include: ingestion of residuals on food or in water, direct accidental ingestion, dermal exposure most often through the workplace or application, and inhalation by volatilization (HC 1993EPA 2005).  The US Environmental Protection Agency (2005) identifies sensitive populations including toddlers and pregnant women; however, individuals producing or using the chemical have potential for exposure.  Toxicological research on 2,4-D often focuses on its potential association with cancer; however, in a recent review of the literature, Burns and Swaen (2012) summarized historical research into four additional human health endpoints including reproductive toxicology, genotoxicity, neurotxicity, and general toxicity.

The effects of 2,4-D on human health have been a long standing public controversy, likely partly due to its historical association with the war-time chemical Agent Orange and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (ACS 2013), and the lack of evidence linking human health effects when used according to guidelines (Burns and Swaen 2012HC 2008).  As a result, both Health Canada and the US Environmental Protection Agency have conducted re-evaluations of 2,4-D in an effort to determine, using scientifically defensible research, the potential risk posed by 2,4-D and the subsequent regulations or management required to minimize that risk (EPA 2005HC 2008).

Despite the large number of studies looking at the toxicity of 2,4-D, the lack of conclusive evidence that 2,4-D is cancer causing (HC 2008) may be contributing to international, national and public perceptions regarding 2,4-D to differ.  The limited epidemiological evidence on which to base guidelines (WHO 2003) and history of public perceptions of 2,4-D has perhaps led to extreme viewpoints on the use of 2,4-D.  For example, the Sierra Club, an environmental activist organization, is opposed to the use of 2,4-D (2005).  Despite reviews of 2,4-D by Health Canada and other world national health organizations to determine the safety of 2,4-D under proper use conditions, there currently exists uncertainty with regard its potential risk to human health.

The purpose of this article is to further discuss the potential human health risks posed by exposure to 2,4-D, and is 2,4-D really ‘bad’ for humans under normal use conditions.  In addition, discussion will explore how the past research has informed the guidelines and reference values used by relevant health organizations.  Due to the relevance of public perception associated with acceptance of risk (Siegrist and Cvetkovich 2000), the current perspectives on the use of 2,4-D by the public and national/international governments will be discussed.  Lastly, a short summary of current research and comment on future direction of 2,4-D research or use will be provided.

References

American Cancer Society. 2013. Agent Orange and cancer.  Website http://www.cancer.org/cancer/cancercauses/othercarcinogens/intheworkplace/agent-orange-and-cancer

Burns, C.J. and G.M.H. Swaen. 2012. Review of 2,4-dichlorophenozyacetic acid (2,4-D) biomonitoring and epidemiology. Critical Reviews in Toxicology. 42(9):768-786

Health Canada. 1993. Fact sheet on the chemical/physical parameters of 2,4-dichlorophenoxyacetic acid. Health Canada.

Health Canada. 2008. Information note: Health Canada releases final re-evaluation decision on 2,4-D. Health Canada.

Siegrist, M. and Cvetkovich, G. 2000. Perception of Hazards: The Role of Social Trust and Knowledge. Risk Analysis. 20: 713–720.

Sierra Club. 2005. Overview of the toxic effects of 2,4-D. Sierra Club of Canada.

Statistics Canada. 2006. Area of commercial fertilizer, herbicides, insecticides and fungicides applied, in Canada from 1996-2006. Statistics Canada.

United States Environmental Protection Agency. 2005. Reregistration eligibility decision for 2,4-D. Prevention, Pesticides and Toxic Substances. EPA 738-R-05-002.

World Health Organization. 2003. 2,4-D in drinking-water: background document for the development of WHO guidelines for drinking-water quality. World Health Organization.


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St. John’s Wort

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The belief that a product that is natural is also safe is a common misconception among users of herbal remedies1. In reality, herbal remedies have the same potential to elicit adverse effects as prescription drugs either directly or indirectly through interactions with other herbs and/or synthetic drugs2. In Canada, approximately 71% of people have reported using some type of herbal therapy including homeopathic drugs, herbal remedies, vitamin supplements and minerals5. Of those only about 12% report having experienced adverse effects from herbal remedy use5. However, less than half of all users of herbal remedies in Canada report adverse reactions5. Other risks are associated with the use of herbal remedies including contamination with heavy metals or over concentrating the pill with the active ingredient during manufacturing, false claims which delay consumers from seeking medical treatment and absent warning labels regarding adverse effects and interactions5. The latter risk is especially true for a product sold in Canada which has risen in popularity across North America and Europe in recent years for the treatment of mild to moderate depression1,2. Specifically, in Canada it is among the top ten most popular herbal remedies6. This product is St. John’s Wort, also known as Hypericum perforatum, an antidepressant that interacts with countless prescription drugs. This reflection will introduce and briefly discuss the risks associated with the use of Hypericum perforatum or St. John’s Wort as it is more commonly known.

St. John’s Wort is a plant of the family Hypericaceae whose extract is used in herbal remedies to treat mild to moderate depression1,2. It has also been used in the treatment of anxiety, sleep disorders, obsessive compulsive disorder, seasonal depression, cancer, gastritis, burns, cuts and abrasions, kidney disease, scabies, hemorrhoids and hypothyroidism1,2. The main ingredients are hypericin and pseudohypericin as well as hyperforin and adhyperforin1. All four ingredients are similar in structure and exert the main pharmacological effects of the herbal medicine1.  However, hypericin is thought to be the active ingredient in the treatment of depression1. The effective dose is 900 mg per day taken as three separate doses (ie. 300 mg taken three times daily) with 0.2-0.3% hypericin in the formula1,2. Animal studies and clinical trials have found St. John’s Wort to be highly efficacious in the treatment of mild to moderate depression when used without any other drugs or herbal medicines1,2. This is because it inhibits the reuptake of serotonin, noradrenaline, dompamine, glutamate and gamma-aminobutyric acid which are neurotransmitters that play a role in mood regulation1. A few clinical studies have found it to be as effective at treating mild to moderate depression as tricyclic antidepressants as well as imipramine (both prescription drugs)1,2. In addition, the herbal remedy has few adverse effects, again when used by itself, and in some cases has been found to have less adverse effects than similar prescription antidepressants; a meta-analysis of 23 studies of clinical trials completed by Russo et al. (2013) found 19.8% reported effects in St. John’s Wort users compared to 35.9% reported effects in users of prescribed antidepressants1,2. The adverse effects that it does have are relatively mild and include mild gastrointestinal irritation, lethargy, allergic reactions, dizziness, nausea, rash and restlessness1. The more serious side effects, photosensitivity and manic episodes, are rare and the latter occurs only in predisposed patients1,2.

Despite a lack of direct adverse effects, St. John’s Wort is still an herbal medicine to be concerned about because of its ability to interact with several prescription drugs. Among the prescription drugs St. John’s Wort can interact with are, central nervous system drugs, bronchodilators, cardiovascular drugs, calcium channel blockers, cardiac inotropic drugs, hypocholesterolaemic drugs, gastrointestinal drugs, oral contraceptives, anti-inflammatories, anti-microbials, antineoplastics, immunosuppresants, oral hypoglycaemic and drugs used in the treatment of HIV1,3. Its ability to interact with these drugs is due to alternate mechanisms of action (MOA) which do not play a role in the treatment of depression. First, St. John’s Wort is a potent activator of CYP enzymes that are involved in the metabolism of drugs1,2. Through this mechanism it can decrease the plasma concentration of prescription drugs taken concurrently with St John’s Wort1,2. Second, it also intensifies the activity of P-glycoprotein (P-gp) which is an adenosine triphosphate-dependent drug transporter that is located throughout the body and plays an active role in drug excretion1. Most prescription drugs are metabolized and excreted using CYP enzymes and P-gp transporters, respectively1. Therefore, the joint use of St. John’s Wort with prescriptions drugs that fall under the category listed above can result in the prescription drugs losing their effectiveness via increased metabolism and clearance1,2. Lastly, in the case of CNS drugs, St. John’s Wort may act synergistically resulting in serotonin syndrome which, in worst-case, can result in a coma1.

Subsequently, the concern with St. John’s Wort is its ability to interact with several prescribed drugs. Often, it is not taken alone but is taken in combination with other prescription medicines1. Its use is under-reported to medical professionals both because they do not ask for the information and because the public does not perceive the use of this herbal medicine as a risk to their health1,2. Furthermore, natural health products (NHP) such as St. John’s Wort are not as rigorously regulated as prescription medicines in Canada which can lead to their misuse and the occurrence of adverse effects which go un-reported4,5. Future reflections will explore in greater depth the interaction of St. John’s Wort with clinical drugs in order to characterize the hazard, the estimated exposure of the population to St. John’s Wort, potential at-risk populations, the perception of risk that the Canadian population has towards this drugs, the estimated risk, the current regulations of NHP and their shortfalls and potential solutions to ensure that the risk of NHPs, particularly, St. John’s Wort are being explored, assessed and evaluated, and made public.

References:

Please note: all references are hyperlinked in-text. However, they are also provided below for your convenience

  1. Russo E., Scicchitano F., Whalley B.J., Mazzitello C., Ciriaco M., Esposito S., PAtane M., Upton R., Pugliese M., Chimirri S., Mammi M., Palleria C. (2013). Hypericum perforatum: Pharmacokinetic, Mechanism of Action, Tolerability, and Clinical Drug-Drug Interactions. Phytother. Res. DOI: 10.1002/ptr. 5050
  2. Ernst E. (2002). The Risk-Benefit Profile of Commonly Used Herbal Therapies: Gingko, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto and Kava. Complementary and Alternative Medicine Series. 136 (1): 42 – 53
  3. University of Maryland Medical Center. (2011). Possible Interactions with: St. John’s Wort. University of Maryland School of Medicine: http://umm.edu/health/medical/altmed/herb-interaction/possible-interactions-with-st-johns-wort
  4. Health Canada. (2012). Drugs and Health Products: A new approach to natural health products. Government of Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/nhp-new-nouvelle-psn-eng.php
  5. Health Canada (2012). Drugs and Health Products: About Natural Health Products. Government of Canada. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/cons-eng.php
  6. World Health Organization. (2002). Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 82


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Human Health Risk Associated With Wind Turbine Noise

Human Health Risk Associated With Wind Turbine Noise

Wind turbines have the potential to contribute to global electricity generation as a clean, emission-free, and increasingly cost-effective energy solution.  Wind power is positioned to contribute, along with other renewable energy sources, increasingly to a reduction in global greenhouse gas emissions while becoming less expensive as technologies improve (Sims et al 2003) Despite this, wind turbines remain controversial due to the perception that they pose a human health risk.  In popular literature, the term “Wind Turbine Syndrome” has been used to describe the perceived suite of health effects associated with wind turbine noise (Knopper and Ollson 2011; Bolin et al 2011) The major issues arise from the wind turbines’ structural features and wind turbine noise (Knopper and Ollson 2011) with the latter largely being the source of public concern. Prolonged exposure to low frequency sound may cause difficulty concentrating, fatigue, sleep disturbance and physiological stress (Bolin et al 2011; Pedersen and Persson Waye 2007).  Popular literature claims more serious symptoms such as cardiovascular disease and epilepsy are associated with wind turbine noise but these effects have not been proven. The potential for health effects has led to the development of minimum setback distances for wind turbines near residential areas.  For example, the Ontario Renewable Energy Approval (REA) Regulation states that “a minimum setback distance of 550 m must exist between the centre of the base of the wind turbine and the nearest noise receptor”.  The 550 m distance was developed through noise modeling under worst-case conditions to give a conservative estimate of the required distance to attain an A-weighted sound level of 40 decibels (Ontario Ministry of the Environment).

 In regards to the construction of wind turbines, these conflicting sources of information have often led to reluctance of local residents. “Not in my backyard” (NIMBY) is a common term cited in the literature in reference to the feelings of people living in areas where wind turbines have been proposed.  In fact, wind turbine noise has been shown to annoy people who can see them more than people who cannot. In addition, people who benefit economically from the wind turbines report less annoyance due to noise than others (Pedersen et al 2009).  Clearly the uncertainty surrounding wind turbine noise is problematic.  This is exacerbated by the fact that large wind turbines for energy production are relatively new technology and few scientific studies of potential long-term adverse health effects exist.

 

Noise with infrasound (1–20 Hz) and low frequency (20–200 Hz) components, such as that associated with wind turbines, may be more disruptive to the health and well-being of humans than sounds with higher frequencies (Bolin et al 2011).  Various studies have shown that loudness and annoyance increases more rapidly with increasing sound pressure for low frequency sounds than those with higher frequencies (Moller and Pedersen 2004, Leventhall 2004).  While low frequency noise or infrasound is emitted by other common sources (vehicular road traffic, air transportation and industry) wind turbine noise has been perceived to be more bothersome, likely due to the “swishing” sound caused by the rotation of the blades, variability (i.e. from wind speed changes) and lack of nighttime abatement (Pedersen et al 2009).  A review by Salt and Hullar 2010 is often cited as proof of adverse effects caused by wind turbine noise.  This paper, which focuses on the effects of infrasound, suggests that infrasound generated by wind turbines has the potential to causes changes to the human inner ear resulting in adverse health effects. Bolin et al 2011 and Knopper and Ollson 2011 both state that the lack of empirical evidence connecting this statement with wind turbine noise experienced at the residential level discredit this finding.  Bolin et al 2011 also argue that despite the existence of two published studies showing potentially damaging levels of infrasound being emitted from wind turbines, these studies were conducted at distances much closer to the turbines than minimum set-back distances.  Thus, noise from these studies could not possibly be at the same level it would be near residential homes.

 

It is difficult to sort out which residents are expressing the NIMBY attitude and which residents are truly sensitive to wind turbine noise such that their health is affected.  Most studies state “annoyance” as the main form of discomfort to people living in the vicinity of wind turbines while evidence for other health effects is lacking, although there has been some correlation between wind turbine noise and sleep disturbance (Bolin et al 2011).  Chronic, long term exposure to something causing stress and sleep disturbance such as wind turbine noise, could potentially lead to cardiovascular problems (Bolin et al 2011).  In addition, there are members of the population who are more sensitive to sound than others, thus the potential for such health effects shouldn’t be dismissed.  While the two recent review papers cited here (Bolin et al 2011and Knopper and Ollson 2011) agree that evidence of serious health problems caused by wind turbine noise is lacking, few, if any, long term studies exist.  The collection of long term data from residents living near wind farms is warranted to determine if chronic effects exist in those exposed to low frequency noise emitted from wind turbines.

 

Author’s note:

This showed up on CBC news this morning: http://www.cbc.ca/news/canada/saskatchewan/story/2013/09/11/saskatoon-community-wind-meeting.html.  Would you support wind power in your community?

 


15 Comments

EDC Properties of Cadmium

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The topic I have chosen to explore is how the metal cadmium (Cd) may potentially result in endocrine disruption. Endocrine disrupting compound (EDC) are those that have the potential to alter hormone pathways that regulate reproduction (Arcand-Hoy and Benson 1998). They have investigated widely in the literature as have the release of metals through anthropogenic activities.  Cadmium is a naturally occurring metal but it is not essential in normal cellular processes so exposure and uptake of Cd can have adverse effects. Cadmium exposure can occur through ingestion of food or water containing Cd as well as inhalation. Inhalation exposure occurs most notably through cigarette smoke but also from coal burning. Cadmium can be food in food that is grown in soils containing either naturally higher Cd levels or in areas where the soil has been increased through anthropogenic uses (Silva et al. 2011).

Cadmium has been identified as a carcinogen by the WHO and is a pollutant considered to be of worldwide concern. It has also been linked to testicular and breast cancer (Pan et al. 2010). As well as having impacts on sperm quality and quantity in human males and implantation success and oocyte development in animal models (Thompson and Bannigan 2008; Pant et al. 2013). So ultimately my goal during these reflections is to gain a more through and clear understanding of the role Cd may play in endocrine disruption and more specifically on how it may affect estrogen pathways.

 

Arcand-Hoy LD, Benson WH. 1998. Fish reproducition: An ecologically relevant indicator of endocrine disruption. Environ Toxicol Chem 17: 49-57.

Pan J, Plant JA, Voulvoulis N, Oates CJ, Ihlenfeld. 2010. Cadmium levels in Europe: implcaitons for human health. Environ Geochem Health 32: 1-12.

Pant N. Pant AB, Chaturvedi PK, Shukla M, Mathur N. Gupta YK, Saxena DK. In Press. Semen quality of environmentally exposed human population: the toxicological consequence. Environ Sci Pollut Res

Silva N, Peiris-John R, Wickremasinghe R, Senanayake H, Sathiakumar N. 2012. J Appl Toxicol 32: 318-332.

Thompson J, Bannigan J. 2008. Cadmium: Toxic  effects on the reproductive system and the embryo. Reproductive Toxicology 25: 304-315.