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Those studies ended with increased incidences of alveolar epithelial hyperplasia and alveolar—bronchiolar metaplasia, results that were similar to what was observed in the earlier National Toxicology Program NTP studies Tritscher et al. A 2-year study of F rats exposed to cacodylic acid at 0— ppm and B6C3F1 mice exposed at 0— ppm failed to detect lung neoplasms at any dose Arnold et al. The data indicate that cacodylic acid may act as a tumor-promoter in the lung. The evidence remains limited but suggestive of an association between exposure to at least one COI and the risk of developing or dying from lung cancer.

In the present update, there are new supporting data from the followup studies of mortality in the Hamburg cohort of herbicide producers Manuwald et al. In the past, the most compelling evidence has come from studies of heavily exposed occupational cohorts, including British 2-methylchlorophenoxyacetic acid MCPA production workers Coggon et al.

The most recent findings from the Operation Ranch Hand study Pavuk et al. The American and Australian cohort studies of Vietnam veterans ADVA, a , b , c ; Dalager and Kang, , which presumably cover a large proportion of exposed soldiers, showed higher than expected incidence of and mortality from lung cancer. The main limitations of those studies are that there was no assessment of exposure—as there was in, for example, the Ranch Hand study—and that some potential confounding variables, notably smoking, could not be accounted for.

The committee believes that it is unlikely that the distribution of smoking differed greatly between the two cohorts of veterans, so confounding by smoking is probably minimal. The studies therefore lend support to the findings of the Ranch Hand study. The methodologically sound AHS did not show any increased risk of lung cancer; however, although there was substantial 2,4-D exposure in this cohort Blair et al.

In large part, the environmental studies have not been supportive of an association, although in the cancer-incidence update from Seveso, the highest risks occurred in the most exposed. Also supportive of an association, however, are the numerous lines of mechanistic evidence, discussed in the section on biologic plausibility, which provide further support for the conclusion that the evidence of an association is limited or suggestive.

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one COI and carcinomas of the lung, bronchus, and trachea. ACS estimated that about 1, men and 1, women would receive diagnoses of bone or joint cancer ICD-9 in the United States in and that men and women would die from these cancers Siegel et al.

Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans 50—64 years.

Among the risk factors for bone and joint cancer in adults are exposure to ionizing radiation in treatment for other cancers and a history of some noncancer bone diseases, including Paget disease. The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and bone and joint cancer.

No Vietnam-veteran studies or case-control studies of exposure to the COIs and bone or joint cancer have been published since Update In an update of cancer incidence from through in 2,4-D production workers in the Dow Chemical Company in Midland, Michigan, Burns et al. Similarly, Waggoner et al. The numbers are too small to add significantly to the assessment of bone-cancer risk associated with exposure to the COIs.

One recent study McNally et al. The data on incidence from the cancer registries included 2, osteosarcoma cases and 1, Ewing sarcoma cases. There were essentially no exposure data, but the cases occurred in lower-socioeconomic areas, possibly indicating some association with agricultural exposures. This very large study has no exposure data and thus provides little information that is germane to the task of the present committee. No environmental studies with sufficiently specific characterization of exposure to the COIs and this health outcome have been published since Update No animal studies have reported an increased incidence of bone and joint cancers after exposure to the COIs.

The small amount of new data, in concert with the previous literature, summarized in Table do not indicate an association between exposure to the COIs and bone cancer. On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and bone and joint cancers.

Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that about 6, men and 5, women would receive diagnoses of STS in the United States in and that about 2, men and 1, women would die from it Siegel et al.

The average annual incidence of STS is shown in Table Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers and some inherited conditions, including Gardner syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have been identified as possible risk factors Zahm and Fraumeni, Additional information available to the committees responsible for subsequent updates has not changed that finding.

As seen with Hodgkin lymphoma and non-Hodgkin lymphoma, the available epidemiologic evidence suggests that phenoxy herbicides rather than TCDD may be associated with developing STS. Some of the strongest evidence of an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies conducted in Sweden Eriksson et al.

The studies, involving a total of cases, show an association between STS and exposure to phenoxy herbicides, chlorophenols, or both. The VAO committee concluded that although those studies had been criticized, there is insufficient justification to discount the consistent pattern of increased risks and the clearly described and sound methods used. In addition, a reanalysis of the data by Hardell to evaluate the potential influence of recall bias and interviewer bias confirmed the original results.

Birth date served as a surrogate for potential exposure to pesticides and herbicides; older cohorts represented higher exposure potential. Men born before were much more likely to die from STS, although this finding was based on only three cases. A similar increased risk was seen in the IARC cohort in deaths that occurred 10—19 years after first exposure Kogevinas et al. Smaller studies of workers that are included in the multinational IARC cohort—Danish herbicide manufacturers Lynge et al.

Several studies have reported on STS in relation to living near waste incinerators that release dioxin as a contaminant. Each of those studies found a statistically significant excess of STS, but none showed any direct evidence of human exposure. Veteran studies have not found a significant increase in STS.

Table summarizes the relevant studies. The numbers were too small to add substantially to the assessment of STS risk associated with exposure to Agent Orange—associated chemicals. In the update of mortality in the AHS cohort, Waggoner et al. It is unclear whether this category contained any deaths from STS, but in any case, the resulting SMRs did not differ from expectations generated from the rates of the populations of Iowa and North Carolina.

Men who had STS were compared with the study wide control group 1, by using conditional logistic regression stratified by age and province of residence and further adjusted for medical history measles, rheumatoid arthritis, mononucleosis, whooping cough, or cancer in a first-degree relative. There is some concern that the increase in fibrosarcomas may be associated with the treatment protocol rather than with TCDD. The NTP gavage study NTP, a also found an increased incidence of fibrosarcomas in male and female rats and in female mice.

Previous committees have concluded that the occupational, environmental, and Vietnam-veteran studies showed sufficient evidence to link herbicide exposure to STS. Although confidence intervals in the new cohort studies were broad because of the rarity of observed cases in small samples, that conclusion is consistent with the findings of Ruder and Yiin On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and STS.

Skin cancers are generally divided into two broad categories: Nonmelanoma skin cancers primarily basal-cell and squamous-cell carcinomas have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table The committee responsible for Update first chose to address melanoma studies separately from those of nonmelanoma skin cancer.

Some researchers report results by combining all types of skin cancer without specifying type. The present committee believes that combined information is not interpretable although there is a supposition that mortality figures refer predominantly to melanoma and that high incidence figures refer to nonmelanoma skin cancer ; therefore, it is interpreting data only when results specify melanoma or nonmelanoma skin cancer. ACS estimated that about 44, men and 32, women would receive diagnoses of cutaneous melanoma ICD-9 in the United States in and that about 6, men and 3, women would die from it Siegel et al.

According to one report, more than 3 million cases of nonmelanoma skin cancer ICD-9 , primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year ACS, b ; it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. It estimates that 3, people die each year from nonmelanoma skin cancer ACS, b. Melanoma occurs more frequently in fair-skinned people than in dark-skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks.

The incidence increases with age, more strikingly in males than in females. Other risk factors include the presence of particular kinds of moles on the skin, suppression of the immune system, and excessive exposure to ultraviolet UV radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun-exposure patterns.

In addition to the dermal forms of melanoma, these tumors occur much more infrequently in various tissues of the eye. Excessive exposure to UV radiation is the most important risk factor for nonmelanoma skin cancer; some skin diseases and chemical exposures have also been identified as potential risk factors. Although exposure to inorganic arsenic is recognized as a risk factor for nonmelanoma skin cancer, this does not imply that exposure to cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor.

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancer. Additional information available to the committee responsible for Update did not change that conclusion. The committee responsible for Update considered the literature on melanoma separately from that of nonmelanoma skin cancer and found that there was inadequate or insufficient information to determine whether there is an association between the COIs and melanoma.

The committees responsible for Update , Update , and Update concurred with the findings of Update The committee responsible for Update was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association, so melanoma was left in the latter category.

The committee for Update determined that evidence of an association between exposure to the COIs and melanoma remained inadequate or insufficient to determine whether an association exists. Cypel and Kang compared cause-specific mortality between deployed and nondeployed veterans in the Vietnam-era ACC cohort.

In comparing the deployed with the nondeployed veterans, a moderate but not statistically significant increase in risk of malignant skin cancer was observed in the deployed cohort. In evaluating the use of specific pesticides and melanoma in the AHS, Dennis et al. Updating cancer incidence in the Seveso cohort for the period — Pesatori et al.

Table summarizes the relevant melanoma studies. No Vietnam-veteran studies or environmental studies of exposure to the COIs and melanoma have been published since Update Individual estimates of exposure were derived from a newly developed predictive model that used serum TCDD concentrations recently measured in a subset of the cohort.

An earlier analysis of the data Boers et al. The study provided no useful information on the risk of melanoma mortality in these workers. They reported incident melanomas in private applicators, for an SIR of 0. They reported 92 incident cases in spouses, for an SIR of 1. Using a similar job classification as a surrogate for exposure, they reported 38 deaths compared with 50 expected for an SMR of 0.

In spouses, they reported 10 deaths compared with 13 expected for an SMR of 0. Controls for that study were drawn from a different study, conducted at about the same time in the same geographic region British Columbia , that was designed to investigate the effect of solar UV exposure and plasma organochlorine compounds on risk of non-Hodgkin lymphoma Spinelli et al. The studies were similar in design: Blood was drawn in — for controls and in for cases.

The laboratory analyses were well controlled to ensure comparability. Plasma samples from controls were assayed for 14 PCB congeners and 11 chlorine-based pesticides or their metabolites; after matching on age and area of residence, were available for use in the study.

A total of three cases were not included in the study because of the inability to match with controls. The exposure assessment included 14 PCB congeners dioxin-like mono-ortho PCBs , , and and non-dioxin-like PCBs 28, 52, 99, , , , , , , , and and 11 persistent pesticides. Many of the accepted risk factors for melanoma were found to be associated with the disease in this study. Analysis showed significant associations between PCB congeners and melanoma although they were rather imprecise.

Total PCB concentrations were associated with disease, with a significant dose—response relationship. There was some indication of an association of pesticide exposure with melanoma but it was limited to nonachlor, Mirex, and hexachlorobenzene.

Thus, the study provided evidence of an association between chemicals that have dioxin-like activity and melanoma but with important limitations. First, the number of cases was small, and participation was low, so there is a question of unmeasured bias. In addition, although the authors attempted to control for sun exposure, this is notoriously difficult.

The cases and controls arose from different studies and, although every attempt was made to match them, they may not have been comparable in some respects such as ethnicity. The presence of disease could alter the measured exposures.

The confidence limits of the point estimates are imprecise, and this lessens confidence in their generalizability. In addition, there is little exposure specificity in the association, so it is difficult to interpret in light of the biologic data. Finally, only dioxin-like mono-ortho PCBs were reported, which typically contribute only a small percentage to total TEQs, making it difficult to accurately determine whether an association exists with total TEQs, and the largest associations were found for the non-dioxin-like compounds.

The results with respect to personal application and mixing of herbicides are more pertinent for the committee's purposes, and they are firmly not positive. TCDD and related herbicides have not been found to cause melanoma in animal models. In general, rodents, which are used in most toxicology studies, are not a good model for studying melanoma. TCDD does produce nonmelanoma skin cancers in animal models Wyde et al.

As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation. Recent work in this field has shown that the AHR mediates UVB-induced skin-tanning in a murine model through action on melanocytes; this is evidence that skin pigmentation and potentially the regulatory action of the target cell for melanoma may be affected by TCDD.

Studies of human cells have also confirmed a role of the AHR in regulation of keratinocytes and melanocytes. In human melanocytes, Luecke et al. Finally, it was recently shown in a Han Chinese population that normal genetic variants of the AHR are associated with the occurrence of vitiligo; this strongly suggests that the AHR is associated with melanocyte distribution in humans. No compelling association between the COIs and melanoma was observed in any of the three new occupational studies.

The committee responsible for Update was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association. However, the data from the final AFHS examination cycle indicate that many more melanoma cases were diagnosed in the comparison veterans than in the Operation Ranch Hand veterans.

Consequently, the committee responsible for Update recommended that the final data on the Ranch Hand and comparison veterans be analyzed in a uniform manner to document the full melanoma experience of the AFHS subjects and to permit definitive evaluation of the possible association between the COIs and melanoma. That request remains unaddressed. This is the first update in which any information on ocular melanoma has been identified.

The case-control study of Behrens et al. Because literature searches did not identify any epidemiology studies of ocular melanoma in association with the COIs, the committee submitted an inquiry to Carol and Mark Shields, who responded Data from Shields [] available in the National Academies Public Access Records Office [ http: On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and melanoma dermal or ocular.

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancer, and additional information available to the committee responsible for Update did not change that conclusion.

The committee responsible for Update considered the literature on nonmelanoma skin cancer separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancer.

The committees responsible for Update , Update , Update , Update , Update , and Update did not change that conclusion. No epidemiology studies of exposure to the COIs and basal-cell or squamous-cell cancer have been published since Update There are no new studies on animal models of skin cancer that are relevant to this update. TCDD has been shown to produce nonmelanoma skin cancer in animal models Wyde et al. As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation, but no experiments have been conducted specifically to support this potential mechanism.

In accord with the results of reports previously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancer. On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancer.

Breast cancer ICD-9 for females, ICD-9 for males is the second-most common type of cancer after nonmelanoma skin cancer in women in the United States. ACS estimated that , women would receive diagnoses of breast cancer in the United States in and that 39, would die from it Siegel et al.

Incidence data on breast cancer are presented in Table Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence is higher in whites than in blacks. Established risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after the age of 30 years.

A pooled analysis of six large-scale prospective studies of invasive breast cancer showed that alcohol consumption up to a daily average of 60 g 2. It is generally accepted that breast-cancer risk is increased by prolonged use of hormone-replacement therapy, particularly preparations that combine estrogen and progestins Chlebowski et al. The potential of other personal behavioral and environmental factors including use of exogenous hormones to affect breast-cancer incidence is being studied extensively.

Most of the roughly 10, female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have reached menopause. Given the high incidence of breast cancer in older and postmenopausal women in general, it is expected on the basis of demographics alone that the breast-cancer burden in female Vietnam veterans will increase in the near future. The vast majority of breast-cancer epidemiologic studies involve women, but the disease also occurs rarely in men, with 2, new cases expected in Siegel et al.

Reported instances of male breast cancer are noted below, but the committee's conclusions are based on the studies in women. The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and breast cancer. Additional information available to the committees responsible for Update , Update , Update , Update , and Update did not change that conclusion.

After consideration of a new study with positive findings on an association between 2,4-D exposure and breast cancer in female farmworkers in California Mills and Yang, —in conjunction with the earlier findings of Kang et al. An increase in the incidence of breast cancer in the residents of Zone A in Seveso may be emerging with greater latency Pesatori et al.

Table summarizes the relevant research. No Vietnam-veteran studies of exposure to the COIs and breast cancer have been published since Update One case of male breast cancer was observed in Cohorts 1 and 2, but the residience requirements excluded it from Cohort 3. They had been employed for at least 3 months during — in a chemical plant that produced insecticides and herbicides, including 2,4,5-T, so they had the possibility of exposure to TCDD.

A Cochran-Armitage trend test on deaths from breast cancer according to quartiles of cumulative exposure did not find evidence of a dose—response relationship; the second and fourth quartiles had significantly increased risks, but the third quartile matched the lowest quartile, with only two breast-cancer deaths.

That constitutes a somewhat stronger finding than had previously been reported by Manz et al. An SMR for breast cancer in the 1, PCP production workers including 67 women who had not been exposed to TCDD was derived on a sex-and race-specific basis using 5-year intervals of age and calendar time.

In that the members of the applicator cohort in the AHS are largely men and those in the spouse cohort predominantly women, for this cancer it is the spouses who are more informative. Of the women participating in the earlier study, were reinterviewed. The small size of the cohort curtails the analyses that can be conducted, but the availability of serum TCDD concentrations measured from blood samples gathered fairly soon after the single-substance accident which minimizes uncertainty about what exposure had been experienced and reduces the need for back-extrapolation contributes substantially to the value of the results.

The incidence of breast cancer in Inuits has traditionally been much lower that that in other Western populations, but there has been a notable increase in the frequency in this population over the last several decades. They were matched by age and district to controls assembled in a previous study of serum concentrations of persistant organic pollutants.

The focus of this study was on perfluorinated compounds, but there also was reporting of serum concentrations of 12 PCB congeners—including dioxin-like, mono-ortho PCBs , , and —and overall AHR-mediated transcriptional activity. Therefore, the study results did not provide evidence of an association between dioxin-like activity and the occurrence of breast cancer in this population.

However, since these values are based solely on mono-ortho PCBs, which typically contribute only a small percentage to total TEQs, no conclusions can be drawn. However, TCDD is a demonstrated carcinogen in animals and is recognized as having carcinogenic potential in humans because of the mechanisms discussed in Chapter 4. With respect to breast cancer, experimental data have shown a role of TCDD in carcinogenesis and promotion and evidence of a protective effect, particularly with regard to metastasis.

Studies performed in laboratory animals Sprague-Dawley rats indicate that the effect of TCDD may depend on the age of the animal. For example, TCDD exposure was found to inhibit mammary-tumor growth in the adult rat Holcombe and Safe, but to increase tumor growth in the neonatal rat 21 days old Desaulniers et al.

Other studies have failed to demonstrate an effect of TCDD on mammary-tumor incidence or growth Desaulniers et al. Fenton recently reviewed the literature on TCDD and breast cancer and suggested that a mechanism may be related to endocrine disruption, which might indicate a close association between the development of mammary cancers and mammary gland differentiation. Agents capable of disrupting the ability of the normal mammary epithelial cell to enter or maintain its appropriate status a proliferative, differentiated, apoptotic state , to maintain its appropriate architecture, or to conduct normal hormone estrogen signaling are likely to act as carcinogens Fenton, ; McGee et al.

In that light, it is interesting that postnatal exposure of pregnant rats to TCDD has been found to alter proliferation and differentiation of cells in the mammary gland Birnbaum and Fenton, ; Vorderstrasse et al. A recent study has shown that TCDD directly targets mammary epithelial cells and the surrounding stromal fat cells during pregnancy-induced mammary gland differentiation; this indicates interference with stromal-epithelial cross-talk as one of several underlying pathways Lew et al.

Thus, the effect of TCDD may depend on the timing of the exposure and on the magnitude of gene expression at the time of exposure; TCDD may influence mammary-tumor development only if exposure to it occurs during a specific window during breast development Rudel et al. The breast is the only human organ that does not fully differentiate until it becomes ready for use; nulliparous women have less-differentiated breast lobules, which are presumably more susceptible to carcinogenesis.

Paradoxically, activation of the AHR by dioxin or by the nondioxin ligand indolecarbinol has also been shown to protect against breast cancer by mechanisms that disrupt migration and metastasis Bradlow, ; Hsu et al. Together, those results demonstrate a complicated interplay between the AHR and other nuclear transcription factors that can either stimulate or inhibit breast-cancer growth in a manner that depends on cell-context. TCDD has been shown to modulate the induction of DNA-chain breaks in human breast-cancer cells by regulating the activity of the enzymes responsible for estradiol catabolism and generating more reactive intermediates, which might contribute to TCDD-induced carcinogenesis by altering the ratio of 4-OH-estra-diol to 2-OH-estradiol, a marker of breast-cancer risk Lin et al.

A similar imbalance in metabolite ratios has been observed in pregnant Taiwanese women, in whom the ratio of 4-OH-estradiol to 2-OH-estradiol decreased with increasing exposure to TCDD Wang et al. Expression of CYP1B1—the cytochrome P enzyme responsible for 2-OH-estradiol formation—but not CYP1A1—the one responsible for 4-OH-estradiol formation—was found to be highly increased in premalignant and malignant rat mammary tissues in which the AHR was constitutively active in the absence of ligand Yang et al.

On the basis of recent mechanistic data, it has been proposed that the AHR contributes to mammary-tumor cell growth by inhibiting apoptosis while promoting transition to an invasive, metastatic phenotype Marlowe et al. Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleu-kin-6 IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including breast tissue, so TCDD might promote carcinogenesis in these tissues DiNatale et al.

In the early s, it was suggested that exposure to some environmental chemicals, such as organochlorine compounds, might play a role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast-cancer risk has been studied extensively, especially in the last decade; TCDD and dioxin-like compounds have been among the organochlorines so investigated.

Today, there is no clear evidence of a causal role of most organochlorines in human breast cancer Salehi et al. Because of concerns raised by a combination of a new study that had good exposure assessment and positive findings Mills and Yang, and several earlier studies Kang et al.

After reviewing new studies that had null findings on mortality from breast cancer in the important cohorts of female Vietnam-era veterans Cypel and Kang, and Seveso residents Consonni et al. The committee for Update concurred, although the year followup of cancer incidence in Seveso Pesatori et al. The marginal increase in the Hamburg cohort Manuwald et al. The case-control study of Greenland Inuits provided no evidence of an association with dioxin-like activity.

Having considered the new evidence and the results of studies reviewed in previous updates, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association either positive or negative between exposure to the COIs and breast cancer. Additional cancers of the female reproductive system that are infrequently reported separately are cancers of the uterus ICD-9 , placenta ICD-9 , fallopian tube and other uterine adnexa ICD-9 Cervical cancer occurs more often in blacks than in whites, but endometrial and ovarian cancers occur more often in whites.

The incidence of endometrial and ovarian cancers is higher in older women and in those who have family histories of these cancers. Use of unopposed without progestogen estrogen-hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of endometrial cancer. HPV infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer. Use of oral contraceptives is associated with a substantial reduction in the risk of ovarian cancer.

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and female reproductive cancers. Additional information available to the committees responsible for Update , Update , Update , Update , Update , Update , Update , and Update has been sparse and has not changed that conclusion.

Tables , , and summarize the results of the relevant studies on cancers of the cervix, uterus, and ovary, respectively. No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and female reproductive cancers have been published since Update That finding is not informative. Though the yellowing of the skin from indulging in a heavy dose of carrots is seldom serious and will disappear in a few days, if consumption ceases, continued carrot gorging can cause medical problems.

In one unfortunate English health advocate named Basil Brown consumed 10 gallons of carrot juice and took 10, times the recommended RDA of vitamin A in a period of 10 days. Those 10 days were the unfortunate man's undoing, his skin turned bright yellow and he died of severe liver damage, probably from the high intake of Vitamin A tablets.

Here is how the press reported the incident in - Extract from "The Times" - Times 15 February A health food addict who had been drinking up to eight pints of carrot juice a day was bright yellow when he died, an inquest at Croydon. Surrey, was told yesterday.

He just thought it was the right way to eat. He also took vitamin A tablets. A typical day's diet for her husband was: Fabricius, the family's doctor, told the coroner that he had warned Mr Brown against his addiction to vitamin A. He had warned Mr Brown to stop taking vitamin A and had later sent him to a specialist who also warned him. Mr Brown had been '"an intelligent man but he had a very low opinion of doctors ".

Dr David Haler, a pathologist, said that Mr Brown was bright yellow when he died. Vitamin A poisoning, like alcoholic poisoning, produced cirrhosis of the liver. The inquest found that Mr Brown had died from carrot juice addiction.

The death of the 48 year old man was widely reported in the press some years ago. The coroner attributed death to addiction to carrot juice. In this instance, however, the dietary regimen that eventually proved fatal included not only large quantities of carrot juice but also up to six tablets of retinol acetate up to 90 mg retinol daily. A combined overdose of both retinol and carrots is most unusual.

Possible addiction to carrots may have reduced the patients intake of more nourishing food. Eating carrots can become addictive: Eating raw carrots may be as addictive as cigarette smoking, and every bit as difficult to give up, according to research on people who develop serious cravings for the vegetable. The phenomenon of 'raw carrot abuse' and the nervous disorders that come in its wake are described today in the British Journal of Addiction.

Although it has been known since the early s that excessive carrot intake can turn the skin orange, the psychological effects of such behaviour are only just coming to light. One year-old woman patient at a psychiatric clinic in Prague, who was eating a kilogram of raw carrots a day, had to be treated in hospital for 'neurological disturbance'.

Another woman seen by the Ludek Cerny, author of the study, started consuming huge quantities of carrots while pregnant with her first child, and managed to stop for 15 years after the baby was born. The habit resumed after a stomach upset. She resorted to purchasing and eating carrots secretly,' the report says.

Switching to radishes helped her reduce her dependency, and she now survives happily on a carrot-free diet. The third case described in the study concerned a year-old man who sought help to give up tobacco. The author suggests that the psychological dependence arises not only from the carotene contained in the vegetable, but possibly from some other active ingredient. It turned out that they had been eating too many carrots which contain carotene, a yellow pigment and tomatoes lycopene.

The result was orange skins. How many carrots and tomatoes were too many? In one case it was 2 cups of carrots a day plus two tomatoes. When the excessive carrots and tomatoes were eliminated from the diet, the patient's skin returned to its normal colour with no ill effects. Pro-vitamin A is converted to vitamin A in the body. It is true that drinking more than five glasses of carrot juice per week may cause the skin to yellow slightly.

This is simply a manifestation of the toxins that the liver is excreting. As an overall tonic and rejuvenator, carrot juice, in moderation, can't be beat. The good thing about beta-carotene overdosing through over eating carotene rich foods is that the body doesn't convert the excess to vitamin A. If this were the case, serious toxicity problems, such as liver damage, would occur. Instead, the excess carotene accumulates over a period of weeks in the skin, primarily on the palms of hands and feet, lending a yellow-orange hue.

There has never been a case where consumption of very large quantities of carotenoids has been shown to be toxic. Consumption of Vitamin A in the form of retinol in which case it would have come from an animal source can be fatal if taken in large quantities. In the early days of polar exploration some of the adventurers made the mistake of killing polar bears and eating their liver. These explorers died as the result of Vitamin A poisoning. Even a small portion of liver from a polar bear can prove fatal because it contains so much Vitamin A in the form of retinol.

Carotenoids on the other hand must be converted by the body into vitamin A. When the body converts what it needs the conversion process ceases and the body stores the carotenoids until needed at a future date The amount of carotene that causes notable skin colour changes varies, but one study showed that approximately 50 milligrams daily led to discolouration in about 10 days. The skin discolouration is completely harmless, except perhaps to friends who may find this appearance startling.

You are missing out on health benefits from the family of carotenes and other phytochemicals by not eating a variety of vegetables such as tomatoes, kale, spinach, winter squashes, broccoli and romaine lettuce and fruit including apricots, tangerines, watermelon, cantaloupe and grapefruit. Remember that while excess carotene can often cause this condition in children, it is uncommon in healthy adults because their liver should function well enough to convert the beta-carotene to vitamin A and eliminate the rest from the body.

As a rule, spinach juice won't turn you green, beets won't turn you red, carrots won't turn you orange. The skin is one of four organs of elimination in your body. Some toxins will come out there. Did you know the skin is the largest organ in the body? Carotenemia should not to be confused with lycopenemia , a similar condition - an excess of lycopene in the blood. The skin takes on the red colour found in tomatoes. Read more about Vitamin A - Click here. Find out more here about Carotenemia here.

Barbara Ballmer-Weber, MD, and colleagues from University Hospital in Zurich, Paul-Ehrlich-Institut, Langen, Germany and the University of Vienna, sought to confirm sensitization to carrot by conducting several different tests on 26 patients with a history of allergic reactions to carrots.

Two food challenges were performed. The first was a double-blinded, placebo-controlled food challenge DBPCFC , where subjects were given two different drinks: The second food challenge performed was a spit and chew test. If they did not experience a reaction, they chewed and swallowed 5 g, then 10 g, and then 20 g of raw carrot. Skin tests and in vitro blood tests were performed to check for the presence of IgE, the antibody that produces allergic reactions.

In vitro testing was also performed to see if allergic sensitivity to birch pollen initially triggered the sensitivity to carrots in these individuals. In the first food challenge, researchers found that 20 patients reacted to the carrot-containing drink but not the placebo. Four patients responded to neither the carrot-containing drink nor the placebo drink. In the spit and chew test, three of these latter four subjects noted no symptoms. The fourth patient reported symptoms of oral allergy syndrome itching of the throat and mouth after swallowing 5 g of raw carrot.

Researchers found that all patients who had positive DBPCFC's also had positive skin test results to raw carrot, while all patients who had negative DBPCFC's had negative skin tests and did not have subsequent reactions to the ingestion of carrot. Additionally, all of the carrot-allergic patients also had birch pollen specific IgE.

However, in vitro testing of the serum from the carrot-allergic patients revealed that allergic binding could not be blocked by birch pollen proteins. Although these allergic patients produced IgE to both carrot and birch pollens, in vitro testing seemed to discount the theory that exposure to airborne birch pollen always precedes and predisposes allergic patients to the development of carrot allergies.

The AAAAI is the largest professional medical specialty organization in the United States representing allergists, asthma specialists, clinical immunologists, allied health professionals and others with a special interest in the research and treatment of allergic disease. Established in , the Academy has more than 6, members in the United States, Canada and 60 other countries.

The Academy serves as an advocate to the public by providing educational information through its Web site. Click here to go there. There is some evidence that people who are allergic to raw carrots are not allergic to cooked ones. This is because when carrots are cooked, the potentially allergenic proteins within them unravel, rendering them safe from targeting by the immune system. Available to download in Word format from the Museum here.

These studies were published in the peer-reviewed, scientific journal of the American Academy of Allergy, Asthma and Immunology. There are also cases of allergy to Carotene - read more here Daily Express UK report Carrots and their leaves can cause dermatitis in sensitive skins. Or download the extract report here. Peeling carrots and slicing off their tops removes virtually all of these residues. But beware that most of the goodness in carrots is in the skins.

The answer is yes to both questions. Are Carrots more nutritious in their raw state than when cooked? Clearly a raw carrot has more goodness in it when it is raw and therefore you would assume it is the healthiest way to eat it. But unless the carrot is juiced then consumed, the body cannot break down the goodness because of the cellular nature of the carrot. Tests have shown that three percent of the total beta-carotene content is released from raw carrots when consumed in raw pieces.

Dr Kirsten Brandt, an agricultural scientist at Newcastle University, has discovered that the subtle difference between pre-slicing a carrot and boiling it whole could drastically affect the vegetable's nutritional powers. Carrots cooked without being sliced have one quarter more of the anti-cancer compound falcarinol than those that are chopped up first.

Read full article here A substance called falcarinol that is found in carrots has been found to reduce the risk of cancer, according to researchers at Danish Institute of Agricultural Sciences DIAS. Kirsten Brandt, head of the research department, explains that isolated cancer cells grow more slowly when exposed to falcarinol.

When they are boiled using any method the carrots are easier to digest, so it is likely that you take up more of the falcarinol in them lose less of it in the stools. On balance, boiled whole is probably slightly better than raw, but that the difference is small, so what is important is that people should cook the carrots or not according to their preference rather that worry about science in this regard! It has been proved that boiling and steaming better preserves antioxidants, particularly carotenoids, in carrots, than frying, though boiling was deemed the best.

The researchers studied the impact of the various cooking techniques on compounds such as carotenoids, ascorbic acid and polyphenols. Deep fried foods are notorious sources of free radicals, caused by oil being continuously oxidized when it is heated at high temperatures. These radicals, which are highly reactive because they have at least one unpaired electron, can injure cells in the body. The antioxidants in the oil and the vegetables get used up during frying in stabilizing the cycle of oxidation.

Another study in showed that cooking carrots increases their level of beta-carotene. Beta-carotene belongs to a group of antioxidant substances called carotenoids, which give fruits and vegetables their red, yellow, and orange colourings. The body converts beta-carotene into vitamin A, which plays an important role in vision, reproduction, bone growth and regulating the immune system. The downside of cooking vegetables is that it can destroy some of the vitamin C in them.

The reason is that Vitamin C, which is highly unstable, is easily degraded through oxidation, exposure to heat it can increase the rate at which vitamin C reacts with oxygen in the air and through cooking in water it dissolves in water. So in reality, unlike most other vegetables though not all , carrots are more nutritious when eaten cooked than eaten raw except when juiced. Because raw carrots have tough cellular walls, the body is able to convert less than 25 per cent of their beta carotene into vitamin A.

So long as the cooked carrots are served as part of a meal that provides some fat the body can absorb more than half of the carotene. Also, it usual for Carrots to be cut into pieces and eaten after boiling or steaming, but done in this way, half the proteins and soluble carbohydrates will be lost so it is more advisable to cook them whole and then cut up.

Experiments show that eating lightly-cooked carrots is much more beneficial than eating raw carrots, which confirms the ancient wisdom in traditional Chinese medicine. Traditional Chinese medicine practitioners have always recommended that their patients eat lightly-cooked carrots in order to get the best nutritional absorption. Recent research by Dr. Xiangdong Wang at Tufts University shows that beta carotene can change in the human body into a substance called retinoic acid, which is widely used to treat cancers.

Carrots contain a lot of beta carotene, which may help reduce a wide range of cancers including lung, mouth, throat, stomach, intestine, bladder, prostate and breast. Some research indicated beta carotene may actually cause cancer, but this has not proven that eating carrots, unless in very large quantities - 2 to 3 kilos a day, can cause cancer.

In fact, a substance called falcarinol that is found in carrots has been found to reduce the risk of cancer, according to researchers at Danish Institute of Agricultural Sciences DIAS. This substance is a polyacethylen, the amount of falcarinol is slightly higher when eaten raw, but when you cook them it softens the tissues and makes it easier to get them out. You probably get more when you eat them boiled or steamed. Eating raw carrots can help relieve and dissipate stress!

Carrots are more nutritious when cut by a knife! Microwaving may help retain more goodness - Some vegetable cooking methods may be better than others when it comes to maintaining beneficial antioxidant levels, according to a new study in the Journal of Food Science, published by the Institute of Food Technologists.

Results showed that, depending on the vegetable, cooking on a flat metal surface with no oil griddling and microwave cooking maintained the highest antioxidant levels. Fruits and vegetables are considered to be the major contributors of nutritional antioxidants, which may prevent cancer and other diseases.

Because of their high antioxidant levels and low-calorie content, consumers are encouraged to eat several servings of fruits and vegetables daily. Researchers at the University of Murcia and the University of Complutense in Spain examined how various cooking methods affected antioxidant activity by analyzing six cooking methods with 20 vegetables. The six cooking methods were boiling, pressure-cooking, baking, microwaving, griddling and frying.

Their findings showed the following: This research is a little suspect as they have found some changes in the chemical reactivity, without any data indicating a correlation with the biological effect. They could just as well have measured the salt content.

On the basis of current knowledge about microwave radiation, the Agency believes that ovens that meet the FDA standard and are used according to the manufacturer's instructions are safe for use, read more. Cancer Research UK has also researched the effecrts of radiation and microwaves and possible links to cancer, read more. Goodness in the skin - As a rough guide the deeper the orange pigmentation in a carrot the more carotene. So peeling can take away some of the nutritional value some carotene and some trace minerals , if only by volume ie you are making a smaller carrot!

In fact the goodness tends to diminish as you approach the centre, aligned with the lighter colour; so one could put up an arguments for coring rather than peeling! Hence "baby" carrots are usually less nutritious than whole ones. They are shaved and abrasively tumbled. If you go to the USDA Nutritional database and compare raw carrots to baby carrots which are peeled you will see that the raw carrots have higher proportionate levels of Vitamin A and other nutrients.

The majority of the carotenoid content is contained in the Phloem outer flesh. It's not that the outer layer peel of the root is much more nutritious but because of cell breakage for those cells, just below the skin, which are cut through in the process of peeling and scrubbing off the outer layers. The fact that a carrot's peel and its nearby flesh are the same colour is an indicator that the two parts of the vegetable have a similar nutritional value.

The Phloem just beneath skin has a higher concentration of carotenoids than the Xylem, which is evident from the relative colours of the two parts of the root. A diagram of the carrot root is shown here. This academic journal fully researched and reported thus:.

The concentration had a general fall longitudinally from crown to tip although there was a small increase just beyond half-way. The pigmentation of xylem was always less, and varied much more, than that of the phloem but the two were positively correlated. The concentration of carotenols in xylems of different carrots was much more nearly constant than that of carotene.

Among them chlorogenic acid was a major hydroxycinnamic acid. Phenolic content in different tissues decreased from peel, phloem to xylem, while antioxidant and radical scavenging activities in different tissues decreased in same order as the phenolic content and correlated well with total phenolic contents.

The higher level of phenolics and antioxidant properties in carrot peel treated as the waste in the processing industry could be considered for value-added utilization. The Carrot museum recommends you just need to scrub and rinse carrots really well to get rid of the dirt or blemishes. Some people think that pesticides are concentrated in the peel of conventional carrots, but that's not the case.

Since carrots are grown underground, the chemicals get into the soil and can seep into the entire vegetable, so peeling won't necessarily prevent you from consuming pesticides. Bitterness in the skin - A study published in showed that conducted by Danish researchers, a carrot's bitterness is largely concentrated in its peel.

Investigation of bitterness revealed that high sugar content to some extent could mask the bitter perception in carrots. Investigation of bitterness in carrots Daucus carota L. Back to where you came from click here. Carrots are one of the best sources of carotene which is a strong antioxidant. But carrots also contain other phenolic compounds that are antioxidants.

Many people do not realise that numerous phenolic compounds are located in the skin of fruit and vegetables, many of which are removed by peeling prior to processing. The Arkansas researchers were studying the effects of thermal processing cooking on the antioxidant properties of carrots. The carrots peeled or non-peeled were sliced and blanched 2 minutes or 20 minutes , cooked in cans at oC for 75 minutes and then stored for up to 4 weeks.

During the first week of storage the antioxidant properties continued to climb, before declining over the next 3 weeks in storage. At the end of the 4 weeks the processed carrots still had more oxidative power than raw carrots. Heating vegetables, either during processing or cooking, is a way of reducing enzyme activity that can lead to undesirable changes in colour, flavour and texture.

But the heat can also change compounds found in the raw food into other chemically related compounds. The properties of these new compounds may be different as was reported in this carrot cooking experiment.

Raw vegetables may be popular with many people, but this study shows that at least some processed and canned vegetables can be just as nutritious as raw ones. In areas where fresh produce is not available year round, or where frozen vegetables are not practical, canned vegetables are an ideal option.

Journal of Agricultural and Food Chemistry According to the University of Minnesota Extension Service, nearly half of some vitamins may be lost within a few days of harvesting unless fresh produce is quickly cooled or preserved. Within 1 to 2 weeks, even refrigerated produce will continue to lose half or more of some of its vitamins. These features were not present in juveniles, which had convex backs like Asian elephants.

Another feature shown in cave paintings was confirmed by the discovery of a frozen specimen in , an adult nicknamed the "Middle Kolyma mammoth", which was preserved with a complete trunk tip. Rather than oval as the rest of the trunk, this part was ellipsoidal in cross section, and double the size in diameter. The feature was also shown to be present in two other specimens, of different sexes and ages.

The hairs on the head were relatively short, but longer on the underside and the sides of the trunk. It is likely that the woolly mammoth moulted seasonally, and that the heaviest fur was shed during spring. Since mammoth carcasses were more likely to be preserved during autumn, it is possible that only the winter coat has been preserved in frozen specimens.

Modern elephants have much less hair, though juveniles have a more extensive covering of hair than adults. Preserved woolly mammoth fur is orange-brown, but this is believed to be an artefact from the bleaching of pigment during burial.

The amount of pigmentation varied from hair to hair and also within each hair. Two alleles were found: In mammals, recessive Mc1r alleles result in light hair. Mammoths born with at least one copy of the dominant allele would have had dark coats, while those with two copies of the recessive allele would have had light coats.

Woolly mammoths had very long tusks modified incisor teeth , which were more curved than those of modern elephants. The largest known male tusk is 4. Female tusks were smaller and thinner, averaging at 1. The sheaths of the tusks were parallel and spaced closely. About a quarter of the length was inside the sockets. The tusks grew spirally in opposite directions from the base and continued in a curve until the tips pointed towards each other, sometimes crossing.

In this way, most of the weight would have been close to the skull, and there would be less torque than with straight tusks. The tusks were usually asymmetrical and showed considerable variation, with some tusks curving down instead of outwards and some being shorter due to breakage. Calves developed small milk tusks a few centimetres long at six months old, which were replaced by permanent tusks a year later. Tusk growth continued throughout life but became slower as the animal reached adulthood.

The tusks grew by 2. Some cave paintings show woolly mammoths with small or no tusks, but it is unknown whether this reflected reality or was artistic license. Female Asian elephants have no tusks, but there is no fossil evidence that any adult woolly mammoths lacked them. Woolly mammoths had four functional molar teeth at a time, two in the upper jaw and two in the lower. The crown was continually pushed forwards and up as it wore down, comparable to a conveyor belt.

The teeth had up to 26 separated ridges of enamel , which were themselves covered in "prisms" that were directed towards the chewing surface. These were quite wear resistant and kept together by cementum and dentine. A mammoth had six sets of molars throughout a lifetime, which were replaced five times, though a few specimens with a seventh set are known.

The latter condition could extend the lifespan of the individual, unless the tooth consisted of only a few plates. The first molars were about the size of those of a human, 1. The molars grew larger and contained more ridges with each replacement. Distortion in the molars is the most common health problem found in woolly mammoth fossils. Sometimes the replacement was disrupted, and the molars were pushed into abnormal positions, but some animals are known to have survived this.

The teeth also sometimes had cancerous growths. Adult woolly mammoths could effectively defend themselves from predators with their tusks, trunks and size, but juveniles and weakened adults were vulnerable to pack hunters such as wolves , cave hyenas and large felines. The tusks may also have been used in intra-species fighting, such as territorial fights or fights over mates.

Display of the large tusks of males could also have been used to attract females, and to intimidate rivals. Because of their curvature, the tusks were not suitable for stabbing, but may have been used for hitting, as indicated by injuries to some fossil shoulder blades. The very long hairs on the tail probably compensated for the shortness of the tail, enabling its use as a flyswatter , similar to the tail on modern elephants.

As in modern elephants, the sensitive and muscular trunk worked as a limb-like organ with many functions. It was used for manipulating objects, and in social interactions. Like modern elephants, woolly mammoths walked on their toes and had large, fleshy pads behind the toes. Like modern elephants, woolly mammoths were likely very social and lived in matriarchal female-led family groups. This is supported by fossil assemblages and cave paintings showing groups.

It is therefore probable that most of their other social behaviour was similar to that of modern elephants. It is unknown how many mammoths lived at one location at a time, as fossil deposits are often accumulations of individuals that died over long periods of time. It is likely that the amounts varied by season and life-cycle events. Modern elephants can form large herds, sometimes consisting of multiple family groups, and these herds can include thousands of animals migrating together.

Mammoths may have formed large herds more often, since animals that live in open areas are more likely to do this than those in forested areas. Mary Reservoir in Canada, showing that there were in this case almost equal numbers of adults, sub-adults and juveniles.

The woolly mammoth was probably the most specialised member of the family Elephantidae. They had lipopexia fat storage in their neck and withers , for times when food availability was insufficient during winter, and their first three molars grew more quickly than in the calves of modern elephants. The expansion identified on the trunk of "Yuka" and other specimens was suggested to function as a "fur mitten"; the trunk tip was not covered in fur, but was used for foraging during winter, and could have been heated by curling it into the expansion.

It was also suggested that the expansion could be used to melt snow if there was shortage of water to drink, as melting it directly inside the mouth could disturb the thermal balance of the animal. This feature may have helped the mammoths to live in high latitudes. In a study, high-quality genome sequences from three Asian elephants and two woolly mammoths were compared. Differences were noted in genes for a number of aspects of physiology and biology that would be relevant to Arctic survival, including development of skin and hair, storage and metabolism of adipose tissue, and perceiving temperature.

Genes related to both sensing temperature and transmitting that sensation to the brain were altered. One of the heat-sensing genes encodes a protein, TRPV3, found in skin which also affects hair growth. When inserted into human cells, the mammoth's version of the protein was found to be less sensitive to heat than the elephant's.

This is consistent with a previous observation that mice lacking active TRPV3 are likely to spend more time in cooler cage locations than wild type mice, and have wavier hair. There were also several alterations in circadian clock genes, perhaps needed to cope with the extreme polar variation in length of daylight. Similar mutations are known in other Arctic mammals, such as reindeer. Food at various stages of digestion has been found in the intestines of several woolly mammoths, giving a good picture of their diet.

Woolly mammoths sustained themselves on plant food, mainly grass and sedges, which were supplemented with herbaceous plants , flowering plants , shrubs , mosses , and tree matter. The composition and exact varieties differed from location to location. Woolly mammoths needed a varied diet to support their growth, like modern elephants. The two-fingered tip of the trunk was probably adapted for picking up the short grasses of the last ice age Quaternary glaciation , 2.

The trunk could also be used for pulling off large grass tufts, delicately picking buds and flowers, and tearing off leaves and branches where trees and shrubs were present. The "Yukagir mammoth" had ingested plant matter that contained spores of dung fungus. Scientists identified milk in the stomach and faecal matter in the intestines of the mammoth calf " Lyuba ". This is later than in modern elephants and may be due to a higher risk of predator attack or difficulty in obtaining food during the long periods of winter darkness in high latitudes.

The molars were adapted to their diet of coarse tundra grasses, with more enamel plates and a higher crown than their earlier, southern relatives. The woolly mammoth chewed its food by using its powerful jaw muscles to move the mandible forwards and close the mouth, then backwards while opening; the sharp enamel ridges thereby cut across each other, grinding the food. The ridges were wear-resistant to enable the animal to chew large quantities of food, which often contained grit. Woolly mammoths may have used their tusks as shovels to clear snow from the ground and reach the vegetation buried below, and to break ice to drink.

The tusks were also used for obtaining food in other ways, such as digging up plants and stripping off bark. The lifespan of mammals is related to their size, and since modern elephants can reach the age of 60 years, the same is thought to be true for woolly mammoths which were of a similar size.

The age of a mammoth can be roughly determined by counting the growth rings of its tusks when viewed in cross section, but this does not account for their early years, as these are represented by the tips of the tusks, which are usually worn away. In the remaining part of the tusk, each major line represents a year, and weekly and daily ones can be found in between. Dark bands correspond to summers, and it is therefore possible to determine the season in which a mammoth died.

The growth of the tusks slowed when it became harder to forage, for example during winter, during disease, or when a male was banished from the herd male elephants live with their herds until about the age of ten. Mammoth tusks dating to the harshest period of the last glaciation 25—20, years ago show slower growth rates.

Woolly mammoths continued growing past adulthood, like other elephants. Unfused limb bones show that males grew until they reached the age of 40, and females grew until they were At this age, the second set of molars would be in the process of erupting, and the first set would be worn out at 18 months of age. The third set of molars lasted for ten years, and this process was repeated until the final, sixth set emerged when the animal was 30 years old.

When the last set of molars was worn out, the animal would be unable to chew and feed, and it would die of starvation. A study of North American mammoths found that they often died during winter or spring, the hardest times for northern animals to survive. The best-preserved head of a frozen adult specimen, that of a male nicknamed the "Yukagir mammoth", shows that woolly mammoths had temporal glands between the ear and the eye.

The glands are used especially by males to produce an oily substance with a strong smell called temporin. Their fur may have helped in spreading the scent further. Examination of preserved calves show that they were all born during spring and summer, and since modern elephants have gestation periods of 21—22 months, it is probable that the mating season was from summer to autumn.

Evidence of several different bone diseases has been found in woolly mammoths. One specimen from Switzerland had several fused vertebrae as a result of this condition. The "Yukagir mammoth" had suffered from spondylitis in two vertebrae, and osteomyelitis is also known from some specimens. Several specimens have healed bone fractures , showing that the animals had survived these injuries.

The habitat of the woolly mammoth is known as " mammoth steppe " or "tundra steppe". This environment stretched across northern Asia, many parts of Europe, and the northern part of North America during the last ice age. It was similar to the grassy steppes of modern Russia, but the flora was more diverse, abundant, and grew faster. Grasses, sedges, shrubs, and herbaceous plants were present, and scattered trees were mainly found in southern regions.

This habitat was not dominated by ice and snow, as is popularly believed, since these regions are thought to have been high-pressure areas at the time. The habitat of the woolly mammoth also supported other grazing herbivores such as the woolly rhinoceros , wild horses and bison.

The southernmost woolly mammoth specimen known is from the Shandong province of China, and is 33, years old. A DNA study showed there were two distinct groups of woolly mammoths: The two groups are speculated to be divergent enough to be characterised as subspecies. The group that became extinct earlier stayed in the middle of the high Arctic, while the group with the later extinction had a much wider range.

A genetic study showed that some of the woolly mammoths that entered North America through the Bering land bridge from Asia migrated back about , years ago and had replaced the previous Asian population by about 40, years ago, not long before the entire species became extinct. It is unknown whether the two species were sympatric and lived there simultaneously, or if the woolly mammoths may have entered these southern areas during times when Columbian mammoth populations were absent there.

Modern humans coexisted with woolly mammoths during the Upper Palaeolithic period when the humans entered Europe from Africa between 30, and 40, years ago. Before this, Neanderthals had coexisted with mammoths during the Middle Palaeolithic , and already utilised mammoth bones for tool making and building materials. Woolly mammoths were very important to ice-age humans, and human survival may have depended on the mammoth in some areas. Evidence for such coexistence was not recognised until the 19th century.

William Buckland published his discovery of the Red Lady of Paviland skeleton in , which was found in a cave alongside woolly mammoth bones, but he mistakenly denied that these were contemporaries. The engraving was the first widely accepted evidence for the coexistence of humans with prehistoric extinct animals and is the first contemporary depiction of such a creature known to modern science.

The woolly mammoth is the third most depicted animal in ice-age art, after horses and bison, and these images were produced between 35, and 11, years ago. Today, more than five hundred depictions of woolly mammoths are known, in media ranging from cave paintings and engravings on the walls of 46 caves in Russia, France and Spain to engravings and sculptures termed " portable art " made from ivory, antler, stone and bone.

Cave paintings of woolly mammoths exist in several styles and sizes. The French Rouffignac Cave has the most depictions, , and some of the drawings are more than 2 metres 6. There does not seem to be a correlation between the number of mammoths depicted and the species that were most often hunted, since reindeer bones are the most frequently found animal remains at the site. Two spear throwers shaped as woolly mammoths have also been found in France. Woolly mammoth bones were used as construction material for dwellings by both Neanderthals and modern humans during the ice age.

Large bones were used as foundations for the huts, tusks for the entrances, and the roofs were probably skins held in place by bones or tusks. Some huts included fireplaces, which used bones as fuel, probably because wood was scarce. It is possible that some of the bones used for materials came from mammoths killed by humans, but the state of the bones, and the fact that bones used to build a single dwelling varied by several thousands of years in age, suggests that they were collected remains of long-dead animals.

Woolly mammoth bones were also made into various tools, furniture, and musical instruments. Large bones, such as shoulder blades, were also used to cover dead human bodies during burial. Woolly mammoth ivory was used to create art objects. Several Venus figurines , including the Venus of Brassempouy and the Venus of Lespugue , were made from this material. Weapons made from ivory, such as daggers, spears, and a boomerang , are also known.

To be able to process the ivory, the large tusks had to be chopped, chiselled and split into smaller, more manageable pieces. Some ivory artefacts show that tusks had been straightened, and it is unknown how this was achieved. Several woolly mammoth specimens show evidence of being butchered by humans, which is indicated by breaks, cut-marks, and associated stone tools. It is not known how much prehistoric humans relied on woolly mammoth meat, since there were many other large herbivores available.

Many mammoth carcasses may have been scavenged by humans rather than hunted. Some cave paintings show woolly mammoths in structures interpreted as pitfall traps. Few specimens show direct, unambiguous evidence of having been hunted by humans. A Siberian specimen with a spearhead embedded in its shoulder blade shows that a spear had been thrown at it with great force. It shows evidence of having been killed by a large predator, and of having been scavenged by humans shortly after.

Some of its bones had been removed, and were found nearby. Most woolly mammoth populations disappeared during the late Pleistocene and early Holocene , alongside most of the Pleistocene megafauna including the Columbian mammoth. This extinction formed part of the Quaternary extinction event , which began 40, years ago and peaked between 14, and 11, years ago.

Scientists are divided over whether hunting or climate change, which led to the shrinkage of its habitat, was the main factor that contributed to the extinction of the woolly mammoth, or whether it was due to a combination of the two. Whatever the cause, large mammals are generally more vulnerable than smaller ones due to their smaller population size and low reproduction rates.

Different woolly mammoth populations did not die out simultaneously across their range, but gradually became extinct over time. Most populations disappeared between 14, and 10, years ago.

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