Food crops such as peanuts, corn, and wheat are susceptible to contamination
by molds – Aspergillus flavus and Aspergillus parasiticus. Aflatoxin, a
byproduct of these molds, is a potent cancer-causing agent. Long-term exposure
to aflatoxin has been linked to increased incidence of liver cancer.
Click on the buttons on the left to find out more about this carcinogen and its link to cancer development.
In 1960, mold-contaminated peanut meal was shipped from Brazil to England and fed to millions of turkeys, which in turn died of liver toxicity. Aflatoxin – a byproduct of the contaminating molds – was isolated and identified as the cause of the turkey deaths, and has been shown to cause liver cancer in other animals. Today, strict guidelines are in place to regulate the levels of aflatoxin in the U.S. food supply.
Click the forward arrow or the numbers below to find out more about aflatoxin.
John Groopman, Ph.D. is the Chair of the Department of Environmental Health Sciences at John Hopkins Bloomburg School of Public Health. His research focuses on the molecular causes and effects of environmental factors that may lead to the development of cancers. This research has led to the development of biomarkers used in studies of high-risk aflatoxin-hepatitis B populations specifically in China.
Aflatoxin is produced by a variety of molds and these molds contaminate the grains either outside or they can actually penetrate inside the grain and aflatoxin itself is a metabolite, it’s a product the mold produces that is then excreted out and contaminates the grain. The toxicity of aflatoxin and its potency as a carcinogen was recognized very early in the 1960s and as a consequence the U.S. Food and Drug Administration and the U.S. Department of Agriculture put in place regulations very early on in the studies of this compound to regulate the levels of aflatoxin that would be permitted in the food supply. It was further recognized that just the physical examination of a corn grain product or peanut butter, or a peanut product was inadequate to determine if aflatoxin was present and only a specific chemical analysis of the grain or grain product could be performed to determine if aflatoxin was really there.
Thomas Kensler, Ph.D. is a professor at John Hopkins Bloomburg School of Public Health. His research focuses on the molecular mechanisms involved in the development of cancers linked to exposure to environmental carcinogens. This research has led to potential chemopreventative strategies for liver cancer in populations at high risk for aflatoxin exposure.
Aflatoxin is a very lipid soluble molecule so that when we ingest it, it's rapidly absorbed. And it goes first to the liver where there are enzymes that will chemically biotransform it into a very reactive chemical, which attacks with very high preference, our DNA, causing damage to that DNA, mutations, perhaps in genes that enhance our susceptibility to cancer production. Aflatoxin is also a very cytotoxic molecule so it will directly kill some of our liver cells creating a void, if you will, that causes the remaining liver cells to replicate and perhaps grow at a faster rate than we would like. The combination of DNA damage and cell proliferation triggers the liver cancer process.
Mold-contaminated crops can be a serious problem especially in countries where proper storage facilities are limited. In such agricultural communities, exposure to the mold byproduct – aflatoxin – can be long-term, and can happen through crop handling as well as diet.
Long-term exposure to aflatoxin and infection with the hepatitis B virus are the leading causes of liver cancer. Click the forward arrow below to find out more about the world-wide incidence of liver cancer.
John Groopman, Ph.D
Bloomberg School of Public Heath
Liver cancer is the third leading cause of cancer death in the world, upwards of a million people die of liver cancer each year worldwide. Many of these cases of liver cancer are in eastern Asia and Sub-Saharan Africa.
Early epidemiological studies demonstrated that the food supply in areas of the world that had high levels of liver cancer were also areas of the world where staple foods were heavily contaminated with aflatoxin.
We were able to do a large epidemiologic study involving many different collaborators, many different research investigators where we examined over 18,000 people in eastern China who were healthy at the beginning of the study, and as these people began to develop liver cancer we then began to ask questions about what were the factors in their diet or in their other exposure situations that contributed to disease.
From this investigation we were able to find that both aflatoxin and the hepatitis B virus separately were major risk factors for the development of liver cancer, but in those individuals who were exposed to both factors together, there was a very powerful, multiple interaction leading to extremely high risk for the development of liver cancer.
We have a very effective vaccine against the hepatitis B virus, but because the transmission of this virus occurs very early in life, we need to have the resources and the ability to vaccinate the world for the rest of 21st century in order to eliminate this virus as a factor in liver cancer development. Our studies also showed that aflatoxin contributes to the development of liver cancer. And it contributes to the development of liver cancer as a consequence of children who once they are no longer being breastfed start to consume the normal everyday adult diet. And so, the studies that we did that showed that there was this very powerful multiplicative interaction between the virus and aflatoxin, indicated to us that if we could block aflatoxin as a major factor in the development of liver cancer, we would be able to lower risk of individuals. At the same time, there needs to be the public health wherewithal in order to vaccinate populations as the birth rate of a country moves forward. Simply put, there are almost three billion people in the world who are at risk for the development of hepatitis B virus infection. And the economic resources do not exist right now for doing the types of vaccinations that need to be done for all the children who are being born year in and year out. And so, this is one of the big public health challenges that even when we have an effective vaccine you still need the economic resources for vaccination and distribution.
Aflatoxin is a byproduct of mold that can cause DNA damage. With prolonged exposure to aflatoxin, cells accumulate DNA mutations and thus are at increased risk of developing into cancer cells.
Click the forward arrow below to find out more about how aflatoxin damages DNA.
Thomas Kensler, Ph.D
Bloomberg School of Public Health
A lot is known about the mechanisms of activation and action of aflatoxin. It forms a reactive epoxide intermediate, which then forms a covalent bond to the N7 atom of guanine in site-specific sequences within critical target genes leading to mutations, altered function, loss of function of those genes. p53 is a major target for aflatoxin.
Aflatoxin is probably the best example of a carcinogen, a human carcinogen that targets p53. There are multiple hot spots in the p53 gene targeted by different types of carcinogens. Aflatoxin targets a guanine in codon 249 in the p53 gene.
I believe the importance of aflatoxin and the causation of liver cancer results from a life long series of exposures. Intermittent sort of random exposures are not likely to sort of tip the balance and create the cancer cells; our defense mechanisms are pretty good for those very low levels and intermittent levels of exposure. But there is a chronic long-term exposure through the diet in many of these high-risk areas. In turn that means we need a chronic long term commitment to a preventive intervention. We need an intervention that people could take every day or at least several times a week, but not just for weeks to make the problem go away, but for the rest of their lives. For as long as the aflatoxin exposure is there, the need for the countermanding or intervention approach is also very important.
Limiting long-term exposure to aflatoxin – a mold byproduct – can decrease the risk of liver cancer.
Scientists are also investigating the use of inexpensive, safe substances that can block the damaging effects of aflatoxin.
Click on the forward arrow to find out how a chlorophyll derivative can block aflatoxin action.
We’ve been investigating several approaches to try and reduce the impact of unavoidable exposures to aflatoxin. One of our approaches has been to use chlorophyllin, which is a derivative, simple derivative of the pigment chlorophyll, which makes our trees green.
It's actually related to the molecule heme. It's a perforin-like molecule with a metal complexed in the middle of it, in this case it's copper, but it forms ionic charge interactions with planar molecules of which aflatoxin is a good example. So there's ionic bonding between the two.
And the way we believe this molecule works is to actually intercept or form a molecular complex with aflatoxin within our gastrointestinal tract. So, the chlorophyllin and the aflatoxin bind each other up, get passed down the fecal stream. The aflatoxin is never absorbed, never gets to the liver, never initiates the damage that creates our problems.
We believe that if we can increase the consumption of leafy green vegetables in particular, those that are rich in chlorophyll, that we might be able to reduce the amount of aflatoxin that is absorbed.
It's worth pointing out that in our clinical trial we didn't use vegetables to administer the chlorophyllin. We used tablets that contained 100 mg of chlorophyllin and asked our participants to take one tablet 20 minutes before each meal. We then measured for the presence of aflatoxin molecules in their blood and urine and were able to show that those people who took the chlorophyllin tablet instead of a placebo tablet had much lower levels of aflatoxin DNA damage products coming out in their urine.
There is a lot of interest in discovering new classes of chemopreventative agents, and foods, fruits, and vegetables in particular appear to be a very rich source. So, we know of at a hundred natural compounds that work through the molecular mechanism that we're trying to target – increased expression of detoxification enzymes. But, there are many other compounds that work through other pathways that also show great promise. And in fact, perhaps, the greatest promise will come in combinatorial approaches where we take agents with distinct mechanisms of action and put them together to really try and knock down the precancerous cells.