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Toxicology Reflections


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How Much Vitamin D is Safe?

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How Much Vitamin D is Safe?

Vitamin D is a hot topic in health research.  Most of the excitement revolves around its potential to prevent and treat chronic diseases.  This reflection will consider the risks and benefits of vitamin D supplementation.  On one hand, a lack of vitamin D can lead to a nutritional deficiency. On the other hand, too much vitamin D can have toxic effects.  In the end, the question I will pose to the reader and answer for myself is: how much vitamin D supplementation should we take?

Vitamin D is a nutrient that regulates the absorption and metabolism of calcium and phosphate.  It is the only vitamin that can be synthesized, but it is still considered a vitamin because the conversion of cholesterol to vitamin D can only take place when the skin is exposed to ultraviolet (UV) light.  Deficiencies are common when people have little sun exposure and little access to vitamin D rich foods.  Severe deficiencies manifest themselves as rickets in children and osteomalacia in adults.  In both of these conditions, the bones become soft because they lack sufficient mineralized calcium and phosphate.

Vitamin D deficiency is a real concern at latitudes associated with long winters because the population is completely dependent on dietary sources of vitamin D for a large portion of the year.  For example, people cannot synthesize vitamin D from November until February in most of Canada.1  In Saskatoon, Saskatchewan, sun exposure is likely inadequate from October until March.  So, where do Canadians get their vitamin D in the winter?  Milk products and alternatives are enriched with enough vitamin D so that the recommended daily intake (RDI) of vitamin D can be acquired if you eat and drink according to the recommendations in the Canadian Food Guide.  However, there are two problems with this policy.  The first (and most obvious) is that not everyone eats and drinks according to the Canadian Food Guide.  Some ethnic groups that have immigrated to Canada do not drink milk or milk substitutes.  The second problem is that the current RDI may not be sufficient for optimal health.  While the current RDI will certainly prevent rickets and osteomalacia, new studies are indicating that higher levels of vitamin D may be required to prevent cancer and heart disease.2  Low vitamin D levels have also been linked with an increased risk of preeclampsia in pregnant women.3

So how can Canadians get more vitamin D?  While there are some vitamin D rich foods such as liver and egg yolks, vitamin D supplements have become much more popular, partially because it is much easier to control the dose.   Vitamin D supplements are now easily accessible at all pharmacies and many grocery stores.  Vitamin D can be part of a multivitamin or by itself in chewable pills, liquid capsules, or liquid droppers.  There is also a wide array of doses available, ranging from 400 – 50 000 International Units (IU) (10 – 1250μg).4

Naturally, when consumers start to read the labels showing different doses, they will be concerned with original question in this reflection.  How much vitamin D is safe?  The answer is not too little and not too much.  Vitamin D has a typical U-shaped dose-response curve where adverse effects increase at both low and high doses.  Hypercalcemia is the first known adverse effect seen with vitamin D toxicity, but the lowest observable adverse effect level (LOAEL) remains unknown.5  Hypercalcemia can lead to calcification of soft tissues and has been linked with cardiovascular disease.6  It is important to note that these toxic effects only occur with excessive dietary intake or direct injection, not sun exposure.  This is because the sun’s UV radiation acts as a negative feedback system by breaking down excess vitamin D under the skin.5  Another common misconception is that vitamin D causes birth defects.  Vitamin D is not a teratogen, but vitamin D induced hypercalcemia may cause birth defects involving vascular stenosis.7  Consumers need to be aware that is important avoid toxicity as well as deficiency.

Hathcock et al. published a risk assessment indicating that the no observable adverse effects level (NOAEL) for vitamin D is 10,000 IU (250 ug)/day.5  This dose is based on two randomized controlled trials that found no adverse effects in healthy men after 8 and 20 weeks.  The authors recommend that an uncertainty factor should be applied to this NOAEL to account for variation in the population.

After a jointly funded investigation in 2010, the Canadian and American governments applied an uncertainty factor of 10 to this NOAEL for infants (0-6 months) to establish a tolerable upper intake level (UL) of 1000 IU/d.  The UL increases with age: 1500 IU/d for infants (7-12 months), 2000 IU/d for children (1-3 years), 3000 IU/d for children (4-8 years), and 4000 IU/d for children (9+ years) and all adults.8,9  The ULs for vitamin D in Europe are based on the same studies and are very similar: 1000 IU/d for infants (0-12 months), 2000 IU/d for children (1-10 years), and 4000 IU/d for children (10+years) and adults.10

In the United Stated and Canada, the RDIs are 400 IU for infants (0-12 months), 600 IU for children and adults (1-70 years), and 800 IU for seniors older than 70.8,9  The Canadian government advises that dietary intake is adequate for most Canadian but seniors over the age of 50 should take daily vitamin D supplements with 400 IU.  These recommendations are comparatively higher than the guidelines set by the World Health Organization (200 IU for adults and 600 IU for seniors) and most European countries (200-400 IU for adults and seniors).11  These differences are due to differences in perceived health benefits and basic assumptions about sun exposure and dietary habits.

The question remains, are these government recommendations adequate for optimal health? Hathcock et al. report that despite many hours of sun exposure, vitamin D levels in outdoor workers at the end of the summer are equivalent to a daily intake of 2800-4000 IU.5  This supports that a UL of 4000 IU is reasonable.  However, considering that humans have worked outdoors for the vast majority of their existence, it seems reasonable to me that our biological systems are best adapted to sunshine abundant conditions and a higher RDI may be warranted.  While there is no decisive evidence that daily doses higher than the RDIs are beneficial, there is strong evidence that daily doses below 4000 IU pose no harm.  The most reasonable safe solution that I have formulated for myself is to spend time outdoors in the summer and to take a daily vitamin supplement of 1000-2000 IU in the winter (October-March).

In summary, this reflection has looked at the risks and benefits of vitamin D supplementation. I believe that dietary sources of vitamin D and sunlight exposure are adequate for me in the summer, but taking vitamin D supplements of 1000-2000 IU/d in the winter is warranted.  What do you think is an appropriate amount of supplementation for optimum health?

References

  1. Sharma, S., Barr, A. B., Macdonald, H. M., Sheehy, T., Novotny, R., & Corriveau, A. (2011). Vitamin D deficiency and disease risk among aboriginal Arctic populations. Nutr Rev, 69(8), 468-478. doi: 10.1111/j.1753-4887.2011.00406.x
  2. Holick, M. F. (2007). Vitamin D deficiency. N Engl J Med, 357(3), 266-281. doi: 10.1056/NEJMra070553
  3. Marya, R. K., Rathee, S., Manrow M. (1987). Effect of calcium and vitamin D supplementation on toxaemia of pregnancy. Gynecol Obstet Invest, 24:38–42. doi: 10.1159/000298772
  4. Haines, S. T., & Park, S. K. (2012). Vitamin D supplementation: what’s known, what to do, and what’s needed. Pharmacotherapy, 32(4), 354-382. doi: 10.1002/phar.1037
  5. Hathcock, J. N., Shao, A., Vieth, R., & Heaney, R. (2007). Risk assessment for vitamin D. American Journal of Clinical Nutrition, 85(1), 6-18. hyperlink
  6. Brandenburg, V. M., Vervloet, M. G., & Marx, N. (2012). The role of vitamin D in cardiovascular disease: From present evidence to future perspectives. Atherosclerosis, 225(2), 253-263. doi: 10.1016/j.atherosclerosis.2012.08.005
  7. Kaushal, M. and Magon N. (2013). Vitamin D in pregnancy: A metabolic outlook. Indian J Endocrinol Metab, 17(1): 76–82. doi: 10.4103/2230-8210.107862
  8. The United State Office of Dietary Suppliments. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  9. Health Canada. http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/vita-d-eng.php
  10. EFSA Panel on Dietetic Products, Nutrition and Allergies (2012). Scientific Opinion on the Tolerable Upper Intake Level of vitamin D. EFSA Journal, 10(7):2813 doi: 10.2903/j.efsa.2012.2813
  11. Doets, E. L., et al. (2008) Current micronutrient recommendations in Europe: towards understanding their differences and similarities. European Journal of Nutrition. 47(1):17-40. doi: 10.1007/s00394-008-1003-5

 

 


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Cardiovascular Disease in Humans as a Result of Exposure to Polycyclic Aromatic Hydrocarbons (PAHs): Is There a Risk?

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        Polycyclic aromatic hydrocarbons (PAHs) are organic compounds with two or more benzene rings (Meador 2010). This group includes about 100 compounds (Neff, 1979). However, thousands of variants are possible when other chemical groups are attached or when a carbon atom is replaced with nitrogen, sulfur or oxygen atoms (Pereira et al. 2009). PAHs are formed during the incomplete combustion of organic matter and fossil fuels (Environmental Canada 1994, Meador 2010).

Humans can be exposed to PAHs through different routes that include ingestion of contaminated food, dermal absorption (Suzuki and Yoshinaga 2007, Varlet et al. 2007, Li et al. 2008), and inhalation of contaminated particles (Environmental Canada 1994). Cigarette smoke has been shown to be an important source of exposure to PAHs in smokers. The concentration of benzo[a]pyrene can range from 0.5 to 7.8 µg/100 cigarette (Environmental Canada 1994). Traditionally, the major concern associated with PAH exposure to humans is carcinogenicity (Baars 2002, Laffon et al. 2006). However, adverse effects on human health can also include non-carcinogenic effects (Burstyn et al. 2005, Xu et al. 2010). In animals, it has been demonstrated that PAHs are able to alter endocrine function (Gentes et al. 2007), suppress the immune system (Trust et al. 1994, Kaminski et al. 2008), cause hemolytic anemia (Troisi et al. 2007), initiate the development of atherosclerotic plaque (Penn and Snyder 1988), elevate blood pressure (Sasser et al.1989), among other pathologies.

Evidence of cardiovascular disease has been documented in humans exposed to PAHs (Burstyn et al. 2005, Everett et al. 2010, Xu et al. 2010). In particular, elevated risk of cardiovascular disease has been demonstrated in occupational exposure to PAHs (revised by Burstyn et al. 2005), resulting in an increased risk of death from complications related to cardiovascular disease (Evanoff et al 1993).Studies investigating employees involved in asphalt paving demonstrated that exposure to benzo[a]pyrene and other PAHs is associated with fatal ischemic heart disease in an exposure-response relationship.The highest relative risk for fatal ischemic heart disease was observed with benzo[a]pyrene exposures of 273 ng/mor higher (Burstyn et al. 2005).

The biological mechanisms of cardiovascular disease associated to PAHs exposure are unclear. However, studies suggest that the mechanism involved in the pathogenesis and development of atherosclerotic plaques are similar or associated with the mechanisms involved in the carcinogenic and mutagenic properties of PAHs (Benditt and Benditt 1973, Albert et al. 1977,). It has been demonstrated that atherosclerotic plaques tend to be monoclonal, suggesting that mutation may be the mechanism for plaque development (Benditt and Benditt 1973). However, some uncertainties related to this possible mechanism remain, once it was verified that mosaic phenotypes in arteries as a consequence of injuries could also result in monoclonal atherosclerotic plaques, without involvement of somatic mutation by PAHs (Benditt and Benditt 1973, Murry et al. 1997).

Additionally, evidence suggests that oxidative stress could also result in the development of cardiovascular disease by causing inflammation, which has been recognized as an important factor in the development of atherosclerosis and cardiovascular disease (Kunzli and Tager 2005, Ridker 2009). Increased levels of inflammatory biomarkers are recognized as important predictors of cardiovascular disease, independent of smoking habits and previous incidence of cardiovascular disease (Danesh et al. 2000, Curb et al. 2003). More specifically, the C-reactive protein is the most studied of inflammatory biomarkers and its ability to predict cardiovascular disease has been confirmed. However, C-reactive protein levels are also associated with diabetes, hypertension, and obesity (Ridker, 2009). Everett et al. (2010) demonstrated that biomarkers of exposure to PAHs in humans were significantly associated with inflammatory biomarkers, indicating that oxidative stress resulting from exposure to PAHs could be a possible mechanism of cardiovascular disease in humans. The urinary PAH biomarker 2-hydroxyphenanthrene at concentration above 148 ng/g creatinine had an odds ratio of 3.17 for elevated cardiovascular disease when compared to urinary concentration below 48 ng/g creatinine. On the other hand, Clark III et al. (2012) did not observe a relationship between exposure to PAHs and biomarkers of cardiovascular disease, such as fibrinogen, homocysteine, and white blood cell count. Both papers analyzed a large scale population sample, and they also adjusted the models for age, race/ethnicity, body mass, and smoking habit. Everett et al. (2010) adjusted the models for presence of diabetes, blood pressure and physical activities. Variables such as age, body mass, smoking habits, blood pressure, etc. can increase the uncertainty of either the biomarker or the exposure to PAHs. This could directly influence the incidence of cardiovascular disease or result in a predisposition to cardiovascular disease unrelated to exposure to PAHs. The difference in results between these studies might be due to differences in the biomarkers that were chosen in each study.

In the United States it has been observed that urinary metabolites of PAHs were significantly associated with self-reported cardiovascular disease for two of the eight PAH metabolites studied (Xu et al. 2010). This research adjusted the results for potential confounding factors, which included demographic characteristics, smoking habit, alcohol consumption, blood pressure, plasma cholesterol, and high-density lipoprotein (HDL). However, diet, exercise activities, and genetic characteristics, which are known predisposing factors for cardiovascular disease were not included in the study. Another important limitation in this study was that the PAH metabolites analyzed were urinary monohydroxy because these metabolites reflect recent exposure to PAHs and might not be representative of chronic exposure scenarios that are of greatest interest. In addition, the urinary metabolites better represent PAHs congeners with 2-3 rings that are mainly excreted in the urine, while  that more potent PAHs with four or more rings are excreted primarily in feces and might not be accurately considered (Ramesh et al. 2004 cited by Everett al. 2010). Xu et al. (2010) observed that different exposure categories, such as age, had a significant effect on the estimated risk of exposure, however, cross-sectional assumptions for different exposure categories is very limited.

According to the class materials and the information provided above, cardiovascular disease resulting from exposure to PAHs should be considered a risk to human health. Exposure to PAHs has the probability to cause significant injury (cardiovascular disease as mentioned), as well as the potential severity can include death. It was stated in class that to be considered a risk, there must be an identified source of hazard, a receptor, and an exposure pathway. PAHs are widespread contaminants with environmental concentrations that are greater in industrialized centres with large population sizes (Environment Canada, 2007). Moreover, it has been observed by Everett et al. (2010) that 16.2% of the sampled US population showed elevated concentrations of PAH metabolites in urine, indicative of elevated levels of exposure to the population.

In conclusion, it has been demonstrated in numerous studies that there is a significant correlation between exposure to PAHs and incidence of cardiovascular disease in humans. However, there are still numerous deficiencies in our understanding of this disease that must be identified in order to accurately characterize and quantify the risk of exposure to PAHs in humans. There is currently limited information on the potential of PAHs to cause cardiovascular disease in low dose exposure. There is limited information on the association of background exposure to PAHs and cardiovascular disease. As mentioned in class, if the mechanism of cardiovascular disease development involves damage to the DNA, as a carcinogenic process, it could not be considered background, since any level of exposure could theoretically cause damage and result in disease. It is necessary to conduct additional studies to better understand the effects and risk of chronic exposure to PAHs in people, such as occupational exposure over a lifetime. Moreover, it would be of significant value to determine the potency of PAHs with a greater number of rings to cause incidence of cardiovascular disease. It would also be important to determine if an increased exposure to PAHs results in an increased risk of other inflammatory diseases and vice-versa.

REFERENCE

 

  1. Albert RE, Vanderlaan M, Burns FJ, Nishizumi M (1977) Effect of carcinogens on chicken atherosclerosis. Cancer Research, 37:2232–2235.
  2. Baars BJ (2002) The wreckage of the oil tanker “Erika” – human health risk assessment of beach cleaning, sunbathing and swimming. Toxicology Letters 128:55-68
  3. Benditt EP, Benditt JM (1973). Evidence for a monoclonal origin of human atherosclerotic plaques. Proceedings of National Academy of Science of the United States of America,70:1753-1756  
  4. Burstyn I, Kromhout H, Partanen T, Svene O, Langard S, Ahrens W, Kauppinen T, Stucker I, Shaham J, Heederik D,Ferro G, Heikkila P, Hooiveld M, Johansen C, Radem BG, Boffetta P (2005). Polycyclic Aromatic Hydrocarbons and Fatal Ischemic Heart Disease. Epidemiology, 16 (6):744-750
  5. Clark III JD, Serdar B, Lee DJ, Arheart K, Wilkinson JD, Fleming LE (2012). Exposure to polycyclic aromatic hydrocarbons and serum inflammatory markers of cardiovascular disease. Environmental Research, 117:132–137
  6. Curb, J.D., Abbott, R.D., Rodriguez, B.L., Sakkinen, P., Popper, J.S., Yano, K., Tracy, R.P. (2003). C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation 107:2016–2020
  7. Danesh, J., Whincup, P., Walker, M., Lennon, L., Thomson, A., Appleby, P., Gallimore, J.R., Pepys, M.B. (2000) Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ, 321(7255):199–204.
  8. Environment Canada (1994) Canadian environmental protect act – Priority substances list assessment report: Polycyclic aromatic hydrocarbons. In: Services MoSa (ed), Ottawa, Ontario
  9. Environment Canada (2007) Environment Canada .Ambient air measurements of polycyclicaromatichydro-carbons (PAH), polychlorinateddibenzo-p-dioxins(PCDD) and polychlorinated dibenzofuransin. Canada (1987–1997). Environmental Technology Center Report, 2007.
  10. Evanoff BA, Gustavsson P, Hogstedt C (1993) Mortality and incidence of cancer in a cohort of Swedish chimney sweeps: an extended follow up study. British Journal of Industry Medicine 50:450-459
  11. Everett CJ, King DE, Player MS, Matheson EM, Post RE, Mainous III AG (2010). Association of urinary polycyclic aromatic hydrocarbons and serum C-reactive protein. Environmental Research,  110:79–82.
  12. Gentes M-L, McNabb A, Waldner C, Smits JEG (2007) Increased thyroid hormone levels in tree swallows (Tachycineta bicolor) on reclaimed wetlands of the Athabasca oil sands. Archives of Environmental Contamination and Toxicology 53:287-292
  13. Kaminski NE, Kaplan BLF, Holapple MP (2008) Toxic responses of the immune system. In: Klaassen CD (ed) Casarett and Doull’s Toxicology – The Basic Science of Poisons.
  14. Kunzli and Tager, 2005 Kunzli N, Tager IB (2005) Air pollution: from lung to heart. Swiss Med Wkly, 135:697–702.
  15. Laffon B, Fraga-Iriso R, Pérez-Cadahía B, Méndez J (2006) Genotoxicity associated to exposure to Prestige oil during autopsies and cleaning of oil-contaminated birds. Food and Chemical Toxicology 44:1714-1723
  16. Li et al., 2008 Li Z, Sandau CD, Romanoff LC, Caudill SP, Sjodin A, Needham LL (2008) Concentration and profile of 22 urinary polycyclic aromatic hydrocarbon metabolites in the US population. Environ Research, 107:320–31.
  17. Meador JP (2010) Ecotoxicology: a derivative of encyclopedia of ecology. In: Jorgensen SE, Fath BD (eds) Ecotoxicology: a derivative of encyclopedia of ecology. Elsevier, San Diego, California
  18. Murry CE, Gipaya CT, Bartosek T (1997) Monoclonality of smooth muscle cells in human atherosclerosis. The American Journal of Pathology, 151:697-705
  19. Neff J M (1979) Polycyclic aromatic hydrocarbons in the aquatic environment: sources, fates, and biological effects. Applied Science, London.
  20. Penn A, Snyder C. (1988) Arteriosclerotic plaque development is ‘promoted’ by polynuclear aromatic hydrocarbons. Carcinogenesis, 9:2185-2189
  21. Pereira MG, Walker LA, Wright J, Best J, Shore RF (2009) Concentrations of Polycyclic Aromatic Hydrocarbons (PAHs) in the Eggs of Predatory Birds in Britain. Environmental Science and Technology 43:9010-9015
  22. Ridker, P.M. (2009) C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clinical Chemistry 55(2):209–215.
  23. Sasser LB, Lundstrom DL, Zangar RC (1989). Elevated blood pressure and heart rate in rats exposed to a coal-derived complex organic mixture. Journal of Applied Toxicology, 9:47-52.
  24. Suzuki K, Yoshinaga J (2007) Inhalation and dietary exposure to polycyclic aromatic hydrocarbons and urinary 1-hydroxypyrene in non-smoking university students. International Archives of Occupational Environmental Health, 81:115–21.
  25. Troisi G, Borjesson L, Bexton S, Robinson I (2007) Biomarkers of polycyclic aromatic hydrocarbon (PAH)-associated hemolytic anemia in oiled wildlife. Environmental Research, 105:324-329
  26. Trust KA, Fairbrother A, Hooper MJ (1994) Effects of 7,12-dimethylbenz[a]anthracene on immune function and mixed-function oxygenase activity in the european starling. Environmental Toxicology and Chemistry, 13:821-830
  27. Varlet V, Serot T, Monteau F, Le Bizec B, Prost C (2007) Determination of PAH profiles by GC–MS/MS in salmon processed by four cold-smoking techniques. Food Additives and Contaminantes, 24:744–57.
  28. Xu X, Cook RL, Ilacqua VA, Kan H,Talbott EO, Kearney (2010). Studying associations between urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and cardiovascular diseases in the United States. Science of the Total Environment, 408:943–4948.


19 Comments

Drinking Water Fluoridation

Assessing the risk posed by a substance to human health can be a tremendous scientific challenge. Gathering scientifically sound data on exposure, evaluating all possible adverse outcomes and the levels needed to reach such effects, assessing the uncertainties surrounding the issue, can take years, decades, even generations. Once all that work is done, however, the process is usually fairly simple. A simple comparison of what is believed to be a safe level and what is believed to be out there does the job.

In many cases, the decisions that follow the conclusions reached by the risk assessment are even more challenging than the assessment itself.  This is commonly the case when more than one risk are to be compared at once and against each other, or when the costs and benefits of a certain decision need to be weighed. In these cases, the lines between scientific, political and moral principles start getting blurred.

Probably no human health issue could better exemplify this than Water Fluoridation, or the addition of fluoride to the drinking water supply as a preventive treatment against tooth decay.

In early the 20th century, tooth decay was a major health issue with nearly every individual across most age groups in the United States presenting the disease. (Centers for Disease Control, 1999). No effective measures were available at the time. Those “treated” for the disease by tooth extraction, would soon develop gastrointestinal problems due to poor mastication. Those who didn’t get the treatment, commonly developed serious oral infections and in many cases died of septicemia (Selwitz et al.).

Epidemiological studies in the 30’s and 40’s uncovered a correlation between a dental condition known as “Colorado Brown Stain” and lower incidence of dental caries. Patients with Colorado Brown Stain were usually restricted to areas of naturally high levels of fluoride in water. The teeth of these individuals, although were stained with yellow/brown spots, presented significantly lower numbers of caries. (Ripa, 1993)

The Colorado Brown Stain would later been known as dental fluorosis and its underlying causes would be linked to the reaction of the hydroxyapatite in the teeth enamel with the fluoride on the water to form a harder and more pH-resistant fluoride-rich variant (Aoba and Fejerskov, 2002).

A few years after that discovery, in 1945 the city of Grand Rapids, Michigan, would become the first city in the world to supplement their municipal water supply with fluoride salts. Many US cities followed shortly. The phenomena would make it across the boarder in only one year, and in 1946 Brantford, ON would become the first Canadian city to adopt this strategy.

Since then thousands of cities across the world have opted for this health policy, and currently 16,412 US cities, serving 62.2% of the US population provide some sort of water fluoridation (Bailey W et al., 2008). Other countries suchas United Kingdom, Ireland, Australia and, as mentioned, Canada join the US on this effeort. Some other European countries such as Germany or Finland, implemented water fluoridation for a number of years, but eventually ceased their programmes.

In 1999, The Centre for Control Deaseases in the United Sates, named Water Fluoridation one of the Ten Great Public Health Achievements in the 20th Century (Centers for Disease Control, 1999). The controversy surrounding the real effectiveness, safety and even morality of the policy still continues and it could also be placed among the most contentious public health topics of the century.

During the next weeks, I will explore the different aspects of this controversial issue. From the more scientific aspects such as the  physiological and microbiological processes involved in tooth decay and tooth re-mineralization, the toxicological effects of fluoride, or the exposure levels (both from natural and human sources) to the more socio-political and moral views around the topic.

References

Aoba, T., Fejerskov, O., 2002. Dental Fluorosis: Chemistry and Biology. Critical Reviews in Oral Biology & Medicine 13, 155-170.

Bailey W, Duchon K, Barker L, W., M., 2008. Populations receiving optimally fluoridated public drinking water – United States, 1992–2006. Morbidity and Mortality  Weekly Reports 57, 737–741

Centers for Disease Control, 1999. Achievements in Public Health, 1990-1999:  fluoridation of drinking water to prevent dental caries. Morbidity and Mortality  Weekly Reports, 933-940.

Ripa, L.W., 1993. A half-century of community water fluoridation in the United States: review and commentary. Journal of public health dentistry 53, 17-44.

Selwitz, R.H., Ismail, A.I., Pitts, N.B., Dental caries. The Lancet 369, 51-59.