Published in About Cancer in Africa
M.p. KALLET, D.M Steiner, g.g Steiner,

In a broad sense our health is entirely dependant on our environment. However, this paper will focus on a more narrow range of factors that increase or reduce the cancer incidence rate in Sub-Saharan Africa. On the positive side, cancer incidence rates in Sub-Saharan Africa are generally amongst the lowest in the world.1 In light of the fact that there are more pressing threats to the welfare of the Sub-Saharan population, our knowledge is limited regarding cancer in Africa. However, because cancer is not the most significant health threat to the African people, every effort needs to be taken to study and prevent cancer since inadequate treatment often leads to a high mortality rate for those affected.2

Much of Africa is undeveloped and this fact is borne out with few instances of air pollution being cited as contributing to the cancer incidence rate. Asbestos however has had a significant impact on the cancer incidence rate in Africa.3 Asbestos was discovered in the early 1800’s and from that time was a major export by South Africa. In the early 1900’s a link between asbestos and disease began to emerge and in the 1960’s the link was established between asbestos and mesothelioma. When the cancer incidence rate for lung cancer is evaluated, it is no surprise that the highest lung cancer incidence rates are found in Southern Africa where asbestos mining once employed 20,000 people (table 1). Environmental exposure to asbestos is a significant factor resulting in an increase in the cancer incident rate; however, smoking remains the leading cause of lung cancer in South Africa.4

Unfortunately, safety standards were lax in Africa even after the health threat of asbestos had been established.4 The mining sites continue to be heavily polluted by asbestos while the transportation routes are considered to be moderately polluted.3 The miners were not the only population affected. The Environmental pollution, as a result of poor control of asbestos during transportation and processing, will affect not only the miners but anyone living in the area.5 Due to the large areas involved at both the mines and the transportation routes there is little likelihood of proper cleanup and asbestos is therefore likley to affect the lung cancer incidence rate for the foreseeable future.

A remarkable increase in the incidence rate of Kaposi’s sarcoma has been found in Central and Southern Africa where the AIDS epidemic has hit the hardest.6 However, Kaposi’s sarcoma is not new to Africa. Kaposi’s sarcoma has been shown to have an increased incidence rate in areas with clay soils. Two substances found in clay soils are believed to contribute to an increase in the incidence in Kaposi’s sarcoma. Iron and alumina-silicates have the ability to enter the sweat glands and travel into the lymph system. It is theorized that the toxicity of iron and the inflammatory reaction to alumina-silicates, results in the development of Kaposi’s sarcoma.7 When the AIDS virus is present in combination with the predisposing factors of iron and alumina-silicates the incidence of Kaposi’s sarcoma is significantly increased. Iron and alumina-silicates found in clay soils are believed to gain entry into the lymph systems as a result of working in fine clay soils without adequate foot protection.8 The dissemination of information on the need for foot protection in those areas with a high incidence of Kaposi’s sarcoma and clay soils should reduce the incidence of this disease.

Skin cancer is an environmental disease that has been adequately adapted to by the indigenous population and only plagues more recent immigrants. Skin cancer is very low in the black population but is significant in the South African white population and is largely related to sun exposure.8

Food borne carcinogens have a major impact on the cancer incidence rate in Sub-Saharan Africa. Liver cancer competes with cervical cancer as the most common cancer in West Africa.6 Esophageal cancer is one of the most common cancers in Eastern and Southern Africa.6 Mycotoxins have been found to play a significant role in the initiation of both liver and esophageal cancer.9,10

Liver cancer is frequent in areas of high exposure to aflatoxin and a high prevalence of HBV infection. Aflatoxins are potent carcinogens and, in association with hepatitis B virus are the most significant factors in the initiation of liver cancer in Africa.9 Aspergillus is the fungus commonly found to produce aflatoxin. Fungus such as Aspergillus grows in poorly processed and stored food. The most common foods found to contain large concentrations of aflatoxins are the ground nut products common in western and central Africa.9

Fumonisins appear to be the primary mycotoxins responsible for esophageal cancer in Central, Eastern and Southern Africa.11 Fumonisin is a mycotoxin produced by the fungus Fusarium verticilliodes. Fumonisins are carcinogenic mycotoxins which occur in moldy corn and other common food staples.11 Again, improper processing and storage of food is responsible for the presence of these carcinogens.

Due to the high incidence of liver and esophageal cancer in Sub-Saharan Africa it can be argued that mycotoxins are equal to viral infections as the most significant risk factor for cancer in Africa. In light of the mortality associated with liver and esophageal cancer the implementation of policies to reduce the intake of mycotoxins could have a significant effect on reducing cancer mortality in Sub-Saharan Africa.

Nitrosamines are another group of dietary compounds that play a role in carcinogenesis in Sub-Saharan Africa.12 Tobacco, known for its high levels of nitrosamines, is surely a factor in some cancers.13 Nitrosamines or their precursers are found in many of the foods and medicinal plants consumed in Sub-Saharan Africa.14,15 However, many of the carcinogenic nitrosamines are formed endogenously as a product of normal digestion. In the laboratory, antioxidants have been shown to inhibit the carcinogenic potential of nitrosamines.16,17 Smoking cessation programs to reduce nitrosamine intake and an increase in foods high in antioxidants would appear to be the most effective approach to reducing the effect of nitrosamines on the cancer incidence rate of Sub-Saharan Africa.

Lung, liver and esophageal cancers have established environmental factors that affect the cancer incidence rate on the Sub-Saharan Africa continent. The other groups of cancers that are common in this region are breast, cervical and prostate cancer (table 1). The incidence rates for these cancers do not appear to be precipitated by environmental factors but are largely related to hormonal influences and viral infections.

If the cancers that are related to biologic vectors such as liver, stomach, Kaposi’s sarcoma and cervical cancer are excluded, the black population in Africa has the lowest cancer incidence in the world. However, the white population in Zimbabwe and South Africa exhibit cancer incidence rates similar to their related ancestors in Northern Europe. While it might be appealing to make the assertion that there is a genetic basis for the low cancer incidence rate amongst the black population in Africa, this assertion does not hold up when comparing the cancer incidence rates for blacks in the United States. The cancer incidence rates are reversed in the United States with African Americans having the highest cancer incidence rates of any population in the world. With this remarkable divergence in cancer incidence rates among people of similar genetic makeup, we are provided with an opportunity to examine how the environment might be responsible for indigenous Africans having a very low cancer incidence rate. No matter if we are discussing mycotoxins and liver and esophageal cancer or asbestos and lung cancer we must also ask if the environment is responsible for reducing the cancer incidence rate found in Sub-Saharan Africa.

Around the globe, the cancer incidence rate increases as the latitude increases. Cancer incidence rates are positively correlated with latitude and this holds true for Sub-Saharan Africa.18 However, there is a stronger correlation between temperature and the cancer incidence rate (r = -0.87) than latitude and the cancer incidence rate (r = 0.71).19 The warmer the average high ambient temperature, the lower the cancer incidence rate.19 It is , therefore, likely that the cancer incidence rate is affected by ambient temperature and not latitude.

It is unlikely that a warmer climate directly affects the cancer incidence rate because humans are warm-blooded and maintain a stable body temperature. In order to maintain a stable body temperature a warm-blooded animal must consume greater quantities of water in higher temperatures. While it is unlikely an increase in water consumption could directly affect the cancer incidence rate, it is likely that something in the water could affect the cancer incidence rate. Upon review of the inorganic compounds found in the water supply throughout the world, it has been found that there is an inverse correlation between the concentration of fluoride in the drinking water and the cancer incidence rate (r = -0.75).19

It is believed that Homo sapiens and their ancient ancestors spent millions of years evolving in the Rift Valley area of Eastern Africa. Early man was covered with hair much like his closely related primates. However, as man evolved, he began to loose his hair and develop a more efficient method of maintaining body temperature. One of man’s most significant evolutionary developments was the loss of hair combined with a significant increase in sweat glands. Animals covered with hair have sebaceous sweat glands, which provide effective cooling until the hair is saturated. When hair is saturated cooling efficiency is lost and the animal overheats. As man evolved he lost his hair which allowed him to cool his body through profuse sweating without overheating. Early man could now pursue his prey in the heat of mid day until they overheated allowing him to overtake an otherwise stronger more powerful animal.

The Rift Valley of Sub-Saharan Africa is in the fluoride belt that stretches across northern and eastern Africa into the Middle East, across Pakistan and India, into Southeast Asia and the south of China. The amount of fluoride in the drinking water of the Rift Valley is commonly found to be 10mg/1 and higher. Man’s ability to cool himself during the heat of the day gave him a significant advantage over his prey but also required a much greater water intake. Early man’s significant increased water intake in an area of high fluoride concentrations resulted in a very large intake of fluoride. As early man lost his hair and began to consume larger amounts of water, it is proposed early man took advantage of this large fluoride intake and incorporated fluoride into essential biologic reactions, which differentiates him from other members of the animal kingdom. In the 1930’s it was found that people living in high fluoride areas did not develop dental caries.20 The fluoride stored in the body is deposited in the teeth during development. Also, fluoride excreted in the saliva is deposited on the tooth’s surface. Fluoride reduces the pH necessary to dissolve the crystalline structure of enamel and dentin. If an individual has an adequate supply of fluoride stored in the body, dental caries is prevented. It is proposed that through evolution Homo Sapiens, developed this mechanism of fluoride intake, storage, release and excretion in order to provide the body with a stable supply of fluoride for vital metabolic processes involved in the prevention of disease.

The discovery that fluoride reduces the incidence of caries was made in the early 1900’s.20 In the 1950’s municipal water departments began to add fluoride to the water supply.20 During this time, people developed concerns that fluoride may be carcinogenic. The concern that fluoride might increase the incidence of cancer has prompted studies to determine if fluoride in the drinking water was related to cancer incidence rates.

In 1974 Nixon and Carpenter published a paper comparing standardized mortality ratios in relation to the amount of fluoride in the drinking water. 21 They reported finding a statistically significant negative correlation between the standardized mortality rate and the fluoride content of the water. They concluded that naturally occurring fluoride was likely to reduce cancer incidence. Hoover et al studied fluoride concentration in drinking water as it applied to standard mortality rates in Texas counties. 22 Consistent trends were found for cancers of the buccal cavity, pharynx (males only), esophagus (males and females) and skin cancer (females). All trends indicated a reduction in cancer incidence with increased fluoride concentration. Multiple regression analysis revealed a statistically significant inverse correlation with the fluoride variable in 4 out of 64 tests of significance. Doll and Kinlen studied cancer incidence between 1950 and 1970 in cities with fluoridated water and in cities without fluoridation. When account was taken for age, sex, and ethnic group and the ratio between observed cancer mortality and expected cancer mortality; cancer incidence fell slightly in cities with fluoridated water while showing no change in cities with non-fluoridated water. 23

McGuire et al in a case-control study of osteosarcoma patients found an inverse correlation between fluoride concentration and the incidence of osteosarcoma.24 In 1995 Gelberg et al published a case-control study comparing fluoride exposure and childhood osteosarcoma.25 They found a statistically significant correlation between increased fluoride intake and a decrease in the incidence of osteosarcoma for males. They proposed that fluoride might have a protective effect for males.

In the 1970’s a series of studies were carried out on normal cells treated with various agents known to initiate mutations by inducing chromosomal damage. Vogel reported a strong anti-mutagenic effect of fluoride on mutation induced by Trenimon and 1-phenyl-3, 3-dimethyltriazene in Drosophilia.26 In 1973 Obe and Slacik-Erben reported findings similar to Vogel, and proposed that sodium fluoride exerts its anti-mutagenic action by suppressing events leading to chromosomal breakage.27 In 1976 Slacik-Erben et al reported that chromosomal aberrations induced by Trenimon revealed that pre, simultaneous, and post-treatments of sodium fluoride significantly enhanced the frequency of undamaged mitosis.28 They interpreted their findings as an indication that sodium fluoride had significant anti-mutagenic activity.

Hirano et al studied the in vitro effects of fluoride on cultures of the osteosarcoma cell line UMR 106. The addition of 0.5 mM fluoride resulted in the induction of apoptosis and a decrease in cell proliferation.29 Anuradha et al reported that fluoride causes cell death in human leukemia (HL-60) cells by the activation of caspase-3, which in turn cleaves poly(ADP-ribose) polymerase leading to apoptosis.30

All valid scientific investigations lead to the conclusion that an increase in fluoride intake is associated with a decrease in the cancer incidence rate. Worldwide cancer incidence rates are inversely related to the amount of fluoride in the drinking water.19 The cancer reporting stations with the lowest cancer incidence rate are found in areas with very high fluoride concentrations in the drinking water. The cancer reporting areas with the highest cancer incidence rate are found in areas with very low fluoride concentrations in the drinking water. 19

Cancer is the loss of control of the cell cycle. Throughout the cell cycle, both internal and external factors determine if the cell will remain at rest, begin to divide and multiply or enter into programmed cell death (apoptosis). A tumor develops when the cell looses the ability to regulate the cell cycle and continues to divide and increase in numbers. Cancer develops when the dividing cells begin to invade surrounding tissues and spread throughout the body.

The factors that regulate the cell cycle have only recently begun to be understood. Cells respond to the needs of the organism by reacting to the presence of molecules that come into contact with the cell’s membrane. If the cell has a receptor for a molecule that contacts its membrane, a cell membrane receptor will initiate a reaction that is transmitted into the cell. G proteins are responsible for signal transduction from the cell membrane to other parts of the cell and are essential for proper regulation of the cell cycle.31,32

G proteins (GTP-dependant signal transducers) are GTPases and cycle between their active GTP-bound form and their inactive GDP-bound form.33,34In other words, G proteins have the intrinsic ability to convert GTP to GDP, thereby automatically converting itself from the active GTP form into inactive GDP.35 However, since GTP is much more abundant than GDP there is a predilection for G proteins to bind GTP and remain in its active state.

Inactive G proteins are located inside the cell membrane and are bound to GDP. When external signals such as growth factors, neurotransmitters or hormones react with a receptor on the cell membrane, G proteins transfer this external signal into the cell and activate target/effecter molecules such as adenylate cyclase.35 The stimulation of receptors on the cell membrane causes the release of GDP from the G protein which is replaced with GTP, thereby activating the G protein.

If an external signal is a growth hormone which activates G proteins to signal for cell division, the intrinsic GTPase activity of the G proteins provides a degree of self regulation. However, hydrolysis of GTP to GDP is very slow and inadequate to limit cell division.

Several different proteins bind to and stimulate or inhibit the hydrolysis of GTP to GDP. The proteins that regulate activity of G proteins are identified by various names but the group that has received attention in relation to cancer is the GTPase activating proteins (GAPs). GAPs are produced by tumor suppressor genes that regulate G proteins by facilitating the hydrolysis of GTP to GDP.36 GAPs combine with the active G protein (GTP-bound) and speed up the hydrolysis of GTP to GDP. Therefore, GAPs are powerful inhibitors of G protein signal transduction. If an external molecule stimulates cell division by converting GDP-bound G protein (inactive) to GTP-bound G protein(active) the signal to proceed with cell division is limited in the presence of GAPs.

In the 1990s the structure of Ras G protein and its GAP was elucidated.37 There was no binding when Ras and its GAP were mixed, therefore, Ras-GTP was not hydrolyzed to RasGDP. However, when aluminum fluoride, magnesium fluoride or beryllium fluoride is added, the Ras/RasGAP complex readily forms.38,39 It was also found that for this reaction to occur, it was necessary that free fluoride be available in solution. Ras and its GAP fit together structurally and aluminum fluoride is located between Ras and its GAP. Fluoride is located at a critical location in the Ras/Ras-GAP complex. The ability of the GAP molecule to react with Ras has been shown to be critical for the proper control of the cell cycle.

Genes produce G proteins and their GAPs to closely regulate the cell cycle. However, if a mutation occurs these proteins can loose the ability to regulate the cell cycle and can contribute to the development of cancer.

Molecular oncologists have studied G proteins called Ras and Rho because they are highly oncogenic. It is estimated that mutations in Ras G proteins are associated with 30% of all human cancers. Ras mutations are found in 90% of pancreatic cancers and 50% of colon cancers.40 The Ras G proteins are responsible for signaling cell growth. When a mutation occurs at a critical place on a Ras gene the Ras protein produced by this gene is left in the switched “on” mode and continually stimulates the cell to divide.41

It has been found that a mutation in one oncogene is insufficient to produce cancer. However, if a mutation also occurs in a gene that is involved in the regulation of the mutated gene, uncontrolled cell growth and cancer can occur.42

Mutant RhoGAP effectively forms the transition state complex RhoGDP-AIF-RhoGAP.43 The mutation of arginine to alanine is overcome in the presence of aluminum fluoride. In the presence of aluminum fluoride mutant RhoGAP is as effective as normal RhoGAP in binding to create the RhoRhoGAP complex.43 For cancer to develop multiple mutations must occur in the regulator genes. A mutation in a signaling G protein and a mutation in the corresponding GAP would likely result in cancer. However, if aluminum fluoride is present, mutated GAP molecules may overcome the mutation.

The Rho family of G proteins is down-regulated by an intrinsic GTPase, which is further down-regulated by GTPase-activating proteins (GAPs). RhoGAPs contain an arginine residue that is involved in the catalysis of GTP to GDP. When the RhoGAP is normal, this protein will produce hydrolysis of RhoGTP to RhoGDP 38,000 fold.43 When RhoGAP is mutated with a substitution of the arginine residue to an alanine residue, the RhoGAP will only hydrolyze RhoGTP to RhoGDP 160 fold.43 This mutation significantly reduces the ability of RhoGAP to convert the active RhoGTP G protein to the inactive RhoGDP G protein.

RhoGAPs and RasGAPs form Aluminum fluoride complexes with the RhoGDP and RasGDP which represent analogues of the transition state of Rho and Ras hydrolysis.37,38,44,45 Fluoride has been found to be intimately associated with two areas of the RasRasGAP complex involved with the hydrolysis of GTP to GDP. Fluoride ligands contact the positively charged guanidinum group of Arg789 which is a critical part of the catalytic mechanism.37 Fluoride has also been found to be involved in the stabilization of the switch II region of RasGAP complex. In the RasGAP complex Gln61 contacts one of the fluoride ions contributing to the stability of the transition state.37

The Rho GTP-binding protein Cdc42 has a low intrinsic GTPase activity that is enhanced by its GTPase activating protein Cdc42GAP. Cdc42GAP stabilizes both the switch I and switch II domains of Cdc42 and contributes arginine305 to the active site. Arg305 represents the catalytic arginine and mutation of this arginine leads to a 40 fold loss in catalytic activity.46 However, with Aluminum fluoride in the active site of the Cdc42-Cdc42GAP(R305) complex, it has been found that the mutant is still able to stabilize the transition state of the GTP-hydrolytic reaction. The stabilization of the switch domains explain how dc42GAP(305) mutant is able to stimulate GTP hydrolysis.46

In addition to fluoride’s association with G proteins, fluoride is also known to increase the bio-reactivity of organic compounds. When fluoride is present in sufficient quantities the highly reactive fluoride anion will replace a hydroxyl radical and thereby increase the compounds bio-reactivity. If fluoride is not present the molecule will substitute the fluoride anion with a hydroxyl radical which will allow the molecule to perform its intended function, but at a lower level of activity.

It is proposed that fluoride plays an essential role in the normal control of the cell cycle and also allows the cell to adapt to mutations that might otherwise lead to loss of control of the cell cycle and the development of cancer.

The worldwide concentration of fluoride in the drinking water varies from 0.0mg/1 to 35mg/1. With this variation it is difficult to see how such a critical roll for fluoride could develop. In an effort to understand the development of fluoride in tumor suppression it is necessary to look at how fluoride is handled in the body and how fluoride tumor suppression capabilities might have evolved.

Consumed fluoride will circulate through the body and be either retained by the bones or excreted by the kidneys. Fluoride is taken rapidly into bone by replacing hydroxyl ions in bone apatite. The process by which fluoride enters the apatite crystals occurs by the formation of new bone or by a three stage ion exchange process.

The amount of fluoride in bone is dependent on fluoride intake, age and bone type. Approximately 20% of fluoride consumed by children is retained by the bones.47

Fluoride is released from bone as evidenced by its continuous appearance in the urine after the intake of fluoride has stopped. The release of fluoride from bone when fluoride is not being consumed occurs through the rapid process of ion exchange and the slower process of osteoclastic resorption.

It is proposed that the body has developed this intricate system of fluoride intake, storage, release and excretion in order to maintain a steady level of fluoride in the blood and tissues.

It has been shown that fluoride is involved in the regulation of signal transduction through G proteins in vitro. It has also been shown that a supply of free fluoride ion is needed for binding of the G protein Ras and its GAP in vitro. Furthermore, it has been found that the presence of aluminum fluoride can restore a mutated RhoGAPs binding ability in vitro. It is proposed that the mechanism of fluoride intake, storage, retention and excretion play a vital role in supplying fluoride in proper concentrations in order to properly regulate the cell cycle and prevent cancer.

Upon arriving in Africa, one of the authors of this paper was quickly informed that if he drank the water he would go home in a box. This concern for the water supply throughout Africa appears to have separated foreign immigrants who drink only purified or imported water from the indigenous people who rely on local water sources. The water supply in South Africa is highly treated and is of high purity. The water supply to the major cities in South Africa is provided by reservoirs that collect rainwater and is then highly filtered prior to entering the municipal water supply. Rainwater collected in the reservoirs lacks the mineral content found in water from more natural sources like lakes, rivers or wells. While the majority of Sub-Saharan Africa consumes water very high in fluoride the water supply to the major cities in South Africa contains very little fluoride.

By referring to table 1 it is clear that the white South African has approximately double the cancer incidence rate as the black South African. The assumption is that historically the white population lived in the cities with purified water while the black South African lived outside cities with more natural sources of water. This situation is similar to the situation in New Mexico, USA, where the American Indian population is located in rural areas having a local supply of water with a very high fluoride concentration; and the white population resides in cities with water imported from the Colorado river that is low in fluoride. The white population of New Mexico has one of the highest cancer incidence rates in the world while the American Indian population has one of the lowest cancer incidence rates in the world. Table 1 brings to light the huge impact breast and cervical cancer has on women in all of Sub-Saharan Africa. In Western Africa liver cancer is obviously a primary contender for the most significant cancer affecting the population with afla-toxin as a risk factor. Kaposi’s sarcoma and esophageal cancer pose major threats to Central and Eastern Africa through risk factors associated with clay soils and Fumonisin respectively. Significant lung cancer incidence in South Africa is related to nitrosamines and asbestos. The ordering of cancer incidence reporting stations by temperature allows the grouping of cancer incidence rates geographically which helps to identify factors in the environment that coincide with various cancers.

From an environmental viewpoint, education of the population on proper storage and preparation of their food staples and an effort to clean up the industrial pollution resulting from asbestos mining would have a significant impact on the cancer incidence rate in Sub-Saharan Africa.



Age-standardized cancer incidence rates for Sub-Saharan Africa8 including all cancers with an Age-standardized rate of 10 or above per 100,000. The cancer reporting stations are listed in order of decreasing average high temperature*48 with accompanying latitude.49

Mali (temp 34C; lat 17N)
Male 33.3  17.3 93.5
Female  17 32 15.1  16.6 115
Niger (temp 34C; lat 16N)
Male 16.9 10.8 78.8
Female  25 19.6 115.5
Nigeria (temp 32C; 10N)
Male  19.8 62.2
Female 25.3 19.9 73.4
The Gambia (temp 31C; 13N)
Male 48.9 83.2
Female 29.6  17.6 82.1
Guinea (temp 29C; lat 11N)
Male 37.6 96
Female 15.5 49.6 12.2 117.7
Congo (temp 29C;  lat 1S)
Male 17.2 67.7
Female 22.5 31.7 93.1
Kenya (temp 27C;  lat 1N)
Male 24.5 16.8 10.4 160.3
Female 14.3 25.9 15.5 152.7
Uganda (temp 27C; lat 1N)
Male 37.7 13.3 38.6 159.5
Female 21 40.7 20.5 12.2 168.5
Malawi (temp 26C; lat 13S)
Male 49.9 17.4 10.7 123.9
Female 12 53.1 31.7 10.7 146.4
Zimbabwe (temp 26C;  lat 20S)
Male 50.9 26 12.1 17.2 28.5 10.6 208.6
Female 19.8 53.1 21.6 10.6 10.3 211.9
Namibia (temp 23C;  lat 23S)
Male 15.4 21.8 109.4
Female 25.6 22.2 99.1
S. Africa (temp 23C;  lat 32S)
Male 11.2 23.1 14.3 119.1
Female 13.6 40.3 106.7
Male 25.8 22.2 20.3 15.3 11.8 10.6 41.1 10.1 241.3
Female 62.8 11.9 17.1 14.2 210
Male 19.2 13.5 16 25.4 16.1 171.2
Female 28.1 31.6 130.8
Male 14.2 22.5 13.1 13 11.7 167.1
Female 42.5 20.5 160.1

*The average high temperature was calculated by averaging the annual average high temperature of each weather reporting station in the country.48


BLDR bladder
BRST breast
CRVX cervix
COL colon/rectum
KP Kaposi’s sarcoma
LVR liver
LNG lung
MEL melanoma
MTH mouth
NHL non-Hodgkin lymphoma
OESOP esophageal
PRS prostate
STM stomach
TEMP average high temperature
LAT latitude



  1. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, eds. Cancer incidence in five continents. Volume VII. IARC Sci Publ 1997;(143):I- xxxiv,1-1240.
  2. Somefun OA, Nwawolo CC, Okeowo PA, Alabi SB, Abdul-Kareem FB, Banjo AA, Elesha SO. Prognostic factors in the management outcome of carcinoma of the larynx in Lagos. Niger Postgrad Med J. 2003 Jun;10(2):103-6.
  3. Mzileni O, Sitas F, Steyn K, Carrara H, Bekker P. Lung cancer, tobacco, and environmental factors in the African population of the Northern Province, South Africa. Tob Control. 1999 Winter;8(4):398-401.
  4. McCullock J. Asbestos mining in Southern Africa, 1893-2002. Int J Occup Environ Health. 2003 Jul-Sep;9(3):230-5.
  5. Abratt RP, Vorobiof DA, White N. Asbestos and mesothelioma in South Africa. Lung Cancer. 2004 Aug;45 Suppl 1:S3-6.
  6. Ziegler JL, Simonart T, Snoeck R. Kaposi’s sarcoma, oncogenic viruses, and iron. J Clin Virol. 2001 Feb;20(3):127-30.
  7. Ziegler JL. Endemic Kaposi’s sarcoma in Africa and local volcanic soils. Lancet. 1993 Nov 27;342(8883):1348-51.
  8. Parkin DM, Ferlay J, Hamdi-Cherif H, Sitas F, Thomas JO, Wabinga H, Whelan SL. Cancer in Africa, 2 October 2003 International Agency for Research on Cancer
  9. Turner PC, Sylla A, Diallo MS, Castegnaro JJ, Hall AJ, Wild CP. The role of aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellular carcinoma: A basis for primary prevention in Guinea-Conakry, West Africa. J Gastroenterol Hepatol. 2002 Dec;17 Suppl:S441-8.
  10. Hendricks D, Parker MI. Oesophageal cancer in Africa. IUBMB Life. 2002 Apr-May;53(4-5):263-8.
  11. Turner PC, Nikiema P, Wild CP. Fumonisin contamination of food: progress in development of biomarkers to better assess human health risks. Mutat Res. 1999 Jul 15;443(1-2):81-93.
  12. Mirvish SS, Huang Q, Chen SC, Birt DF, Clark GW, Hinder RA, Smyrk TC, DeMeester TR. Metabolism of carcinogenic nitrosamines in the rat and human esophagus and induction of esophageal adenocarcinoma in rats. Endoscopy. 1993 Nov;25(9):627-31.
  13. Atawodi SE, Preussmann R, Spiegelhalder B. Tobacco-specific nitrosamines in some Nigerian cigarettes. Cancer Lett. 1995 Oct 20;97(1):1-6.
  14. Atawodi SE, Lamorde AG, Spiegelhalder B, Preussmann R. Nitrosation of Nigerian medicinal plant preparations under ‘chemical’ and ‘simulated’ gastric conditions. Food Chem Toxicol. 1995 Jan;33(1):43-8.
  15. Atawodi SE, Maduagwu EN, Preussmann R, Spiegelhalder B. Potential of endogenous formation of volatile nitrosamines from Nigerian vegetables and spices. Cancer Lett. 1991 May 24;57(3):219-22.
  16. Sakata K, Hara A, Hirose Y, Yamada Y, Kuno T, Katayama M, Yoshida K, Zheng Q, Murakami A, Ohigashi H, Ikemoto K, Koshimizu K, Tanaka T, Mori H. Dietary supplementation of the citrus antioxidant auraptene inhibits N,N-diethylnitrosamine-induced rat hepatocarcinogenesis. Oncology. 2004;66(3):244-52.
  17. Ray G, Husain SA. Oxidants, antioxidants and carcinogenesis. Indian J Exp Biol. 2002 Nov;40(11):1213-32.
  18. Kato I, Tajima K, Kuroishi T, Tominaga S. Latitude and pancreatic cancer. Jpn J Clin Oncol 1985;15(2):403-13
  19. Steiner GG. Cancer incidence rates and environmental factors: An ecological study. Journal of Environmental Pathology, Toxicology and Oncology 2002;21(3):205-212
  20. American Dental Association
  21. Nixon JM, Carpenter RG. Mortality in areas containing natural fluoride in their water supplies, taking account of socioenvironmental factors and water hardness. Lancet 1974;2(7888):1068-71
  22. Hoover RN, Mckay FW, Fraumeni JF. Fluoridated drinking water and the occurrence of cancer. J Natl Cancer 1976;57(4):757-68
  23. Doll R, Kinlen L. Fluoridation of water and cancer mortality in the U.S.A. Lancet 1977;1(8025):1300-2
  24. McGuire SM, Vanable ED, McGuire MH, Buckwalter JA, Douglass CW. Is there a link between fluoridated water and osteosarcoma? J Am Dental Assoc. 1991;122(4):39-45
  25. Gelberg KH, Fitzgerald EF, Hwang S, Dubrow R. Fluoride exposure and childhood osteosarcoma: A Case-Control Study. American Journal of Public Health 1995;85(12):1678-83
  26. Vogel E. Strong antimutigenic effects of fluoride on mutation induction by trenimon and 1-phenyl-3,3-dimethyltriazene in Drosophila Melanogaster. Mutation Research 1973;20:339-352
  27. Obe G, Slacik-Erben R. Suppressive activity by fluoride on the induction of chromosome aberrations in human cells with alkylating agents in vitro. Mutation Research 1973;19:369-371
  28. Slacik-Erben R, Obe G. The effects of sodium fluoride on DNA synthesis, mitotic indices and chromosomal aberrations in human leukocytes treated with Trenimon in vitro.Mutation Research 1976;37:253-266
  29. Hirano S, Ando M. Fluoride mediates apoptosis in osteosarcoma UMR 106 and its cytotoxicity depends on the pH. Arch Toxicol 1997;72(1):52-8
  30. Anuradha CD, Kanno S, Hirano S. Fluoride induces apoptosis by caspase-3 activation in human leukemia HL-60 cells. Arch Toxicol 2000;74(4-5):226-30.
  31. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem 1987;56:615-4
  32. Casey PJ, Gilman AG. G protein involvement in receptor-effector coupling. J Biol Chem 1988;263(6):2577-80.
  33. Hall A, Self AJ. The effect of Mg2+ on the guanine nucleotide exchange rate of p21 N-ras. J Biol Chem. 1986;261(24):10963-5.
  34. McGrath JP, Capon DJ, Goeddel DV, Levinson AD. Comparative biochemical properties of normal and activated human ras p21 protein. Nature 1984;310(5979):644-9.
  35. Hall A. The cellular function of small GTP-binding proteins. Science 1990;249:635
  36. Martin GA, Viskochil D, Bollag G et al: The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990;63:843
  37. Scheffzek K, Ahmadian MR, Kabsch W, Weismuller L, Lautwein A, Schmitz F, and Wittinghofer A. The Ras-RasGap complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997 18;277(5324):333-338.
  38. Hoffman GR, Nassar N, Oswald RE, and Cerione RA. Fluoride activation of the Rho family GTP-binding protein Cdc42Hs. J. Biol. Chem. 1998;273(8):4392-4399.
  39. Graham DL, Eccleston JF, Chung CW, Lowe PN. Magnesium fluoride-dependent binding of small G proteins to their GTPase-activating proteins. Biochemistry 1999;38(45):14981-7.
  40. Bos Jl. ras oncogenes in human cancer: a review. Cancer Res 1989;49(17):4682-9.
  41. Ahmadian MR, Zor T, Vogt D, Kabsch W, Selinger Z, Wittinghofer A Scheffzek K. Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proc Natl Acad USA 1999;96(12):7065-70.
  42. Land HF, Parada LF, Wienberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 1983;304:596
  43. Graham DL, Eccleston JF, Lowe PN. The conserved arginine in rho- GTPase-activating protein is essential for efficient catalysis but not complex formation with Rho.GDP and aluminum fluoride. Biochemistry 1999 19;38(3):985-91.
  44. Mittal R, Ahmadian MR, Goody RS, and Wittinghofer A. Formation of a transition-state analog of the Ras GTPase reaction by Ras-GDP, tetrafluoroaluminate, and GTPase-activating proteins. Science 1996;273(5271):115-117.
  45. Ahmadian MR, Mittal R, Hall A, and Wittinghofer A. FEBS
    Lett 1997;408(3):315-318.
  46. Nassar N, Hoffman GR, Manor D, Clardy JC, Cerione RA. Structures of Cdc42 bound to the active and catalytically compromised forms of Cdc42GAP. Nat Struct Biol 1998;5(12):1047-52.
  47. Zohouri FV, Rugg-Gunn AJ. Total fluoride intake and urinary excretion in 4-year-old Iranian children residing in low-fluoride areas. Br J Nutr 2000;83(1):15-25.