Meat And The Pathology Of Human Disease

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When considering whether a causative role of meat in fatal disease is biologically plausible, it is important to note that meat, as consumed in the typical human diet, contains a number of nutritional and other components that may be independently causal. Specifically, as a food group, meats can be reduced to components based on macronutrients, micron-utrients, and substances present in the ingested meat due to commercial feedlot practices and methods used in the preservation, processing, handling, and cooking of meats. These components of meat and their possible relation to the development of fatal disease are summarized in Table 7.1 and discussed below.

A. Nutrient Components of Meat

The fat in red meats has been identified as having a very high content of saturated fat (Table 7.2). Thus, based on fat content alone, red meat could be considered an atherogenic risk factor that contributes to coronary heart disease and ischemic strokes. A number of prospective studies have linked red meat intake to higher rates of coronary heart disease and stroke.18-22 Recent laboratory data also raise the possibility that the low polyunsaturated to saturated fat ratio in red meats (Table 7.2) increases the permeability of the cell membrane to insulin receptors and thus increases insulin resistance.23-25 This mechanism suggests that increased red meat intake (relative to other meats or no meat intake) could potentially produce a hyperinsulinemic state that would contribute to a higher risk of diabetes, and perhaps certain cancers (prostate, colon, breast). In this context, it is noteworthy that Snowdon has reported a prospective association between red meat intake and increased diabetes risk,26 a convincing body of evidence implicates red meat intake in colon carcino-genesis,27 and recent evidence also links insulin-like growth factors to an increased risk of cancers of the prostate, colon, and breast.28

2. Protein

Ingested meat protein increases fecal nitrates among omnivores and therefore has long been implicated in the endogenous formation of carcinogenic N-nitroso compounds by the colonic flora. Recently, Bingham et al.29 have demonstrated a threefold increase in the formation of N-nitroso compounds in a feeding trial of eight human subjects who changed from a low-meat (60 g/day of beef, lamb, or pork) to a high-meat (600 g/day of beef, lamb, or pork) diet.

Table 7.1 Nutritional and Other Components of Meat Intake as Possible Risk Factors

Component

Possible Risk Factor for:

References

Nutritional

Meat Fat

Saturated Fat

CVD*, Cancer

18-22

Polyunsatuarated Fat/Saturated

Diabetes, Cancer

23-28

Fat Ratio

Meat Protein

Nitrates

Cancer

29, 83

Heterocyclic Amines

Cancer, CVD

30-40

Total Energy Intake

Cancer, Aging

41-44

Iron

Cancer, CVD

45-61

Phosphorus

Osteoporosis, Fractures

62-67

Other Components

Added to Animals in Commercial

Feedlots

Hormones (estradiol,

?

68-74

progesterone, testosterone,

trenbolone acetate, zeranol)

Antibiotics

Bacterial infection by

75, 76

Antibiotic-resistant strains

Feed supplemented with

Creutzfeldt-Jakob variant

77-82

rendered animal tissue that is

infected with prion disease

Formed/Added during Preserving,

Processing, and Handling

Nitrates, Nitrites

Cancer

83

Salting, Curing

Cancer

84, 85

E. Coli

Infection

86

Salmonella

Infection

86 ,87

Trichinellosis

Infection

86

Formed/Added during Cooking**

Benzo[a]pyrenes and other

Cancer

83, 88

Polycyclic Aromatic

Hydrocarbons

  • CVD = cardiovascular disease
  • Heterocylic amines not listed since covered under meat protein

Data indicating that the cooking of meat protein produces certain heterocyclic amines has often been cited as a possible mechanism whereby increased meat protein intake can increase risk of colon cancer and

Table 7.2 Nutrient Content of Meats and Foods that Typically Replace Meats in the Human Diet

Foods that Typically Replace Meats Meats in the Human Diet

Table 7.2 Nutrient Content of Meats and Foods that Typically Replace Meats in the Human Diet

Foods that Typically Replace Meats Meats in the Human Diet

1/2

1/2

1/2

3 oz

3 oz

3 oz

3 oz

cup

cup

cup

3 oz

Pinto

Veggie

Beef

Pork

Poultry

Fish

Lentils

Beans

Tofu

Burger

Fats

Saturated (g)

9.3

6.5

3.0

1.07

0.05

0

0.9

0.7

Polyunsaturated (g)

0.8

2.0

2.4

2.77

0.17

0.5

3.4

2.8

Calories (kcal)

264

238

187

155

114

110

94

151

Iron (mg)

1.4

0.8

1.2

0.9

3.3*

2.7*

6.7*

1.5*

Phosphorus (mg)

131

187

118

217

178

0

120

157

Calcium (mg)

6.1

8.5

9.3

12.8

18

40

138

61.2

Fiber (g)

0

0

0

0

7.8

7

1.5

5.1

  • non-heme iron
  • non-heme iron perhaps cardiovascular disease.30 Specifically, four out of the 20 known heterocyclic amines (IQ(2-Amino-3,4-dimethylimidazo[4,5-/lquinoline), MeIQ (2-Amino-3,4-dimethylimidazo[4,5-/lquinoline), MelQx (2-Amino-3,4-imethylimidazo [4,5-/lquinoline), and PhiP(2-Amino-3,4-dimethylimi-dazo[4,5-/lquinoline)) are formed from a reaction that occurs at normal cooking temperatures between the creatinine and amino acids in all meats, including fish.

Do these four meat-derived heterocyclic amines contribute to the pathology of commonly occurring diseases? There is a growing body of evidence that suggests that the IQ, MeIQ, MeIQx, and PhiP derived from cooked meat protein have mutagenic, carcinogenic, and cardiotoxic effects.

Beginning in 1977 with the seminal work of Sugimura et al. at the National Cancer Center in Tokyo, a number of studies have documented a potent mutagenicity of IQ, MeIQ, MelQx, and PhiP.3031 For example, these studies indicate that MeIQ can produce from 102 to 109 times more mutations than other well-known food-based mutagens such as aflatoxins, benzo[alpyrene, and nitrosamines. Further suggestions that heterocyclic amines are directly causal comes from rodent models32,33 indicating that, in tumors that were induced by MeIQ and PhiP, the mutations occurred in well-known cancer- and colon cancer-related genes (p53, H-ras, Apc). That heterocyclic amines might have causal effects on premalignant lesions is also supported by rodent studies that identify the carcinogenicity of IQ, MeIQ, MeIQx, and PhiP at sites in the liver, GI tract, and breast.30,34 A few studies in rodents and primates have raised the possibility that IQ can induce mutations that contribute to cardiac myocyte hypertrophy, atrophy, and necrosis.35-37 Such mechanisms of action raise the possibility that meat-derived heterocyclic amines may also contribute to cardiovascular disease.

When considering the possible causal effect of meat protein-derived heterocyclic amines, it is important to note that the final acetylation step in endogenous formation of these compounds is catalyzed by an enzyme, N-acetyltransferase(NAT2), that is regulated by the NAT2 gene. It has been shown that molecular variants of the NAT2 gene produce commonly occurring fast acetylator and slow acetylator phenotypes, with the former being implicated in a faster rate of production of heterocyclic amines.38 Thus, it is reasonable to assume that the combination of fast acetylator phenotype and high meat intake might be components of a multifactorial pathology. This combination has been shown to increase the risk of colon cancer in a few recent case-control and cohort studies.39,40

3. Energy

The data in Table 7.2 indicate that meats can contain up to twice the calories of the equivalent serving of non-meat items (i.e., tofu, legumes) that typically replace meats in the diet. These data may explain why the prevalence of obesity appears to be substantially lower among those following meatless diets.41 These data also raise the possibility that lower mortality rates observed among those consuming meatless diets may be attributable to the causal effect of lower energy intake.

At present, much of the data directly relating caloric restriction to greater longevity comes primarily from rodent studies42 indicating that rodents undergoing caloric restriction experienced up to 30% increases in life span relative to those fed ad libitum. Also noteworthy is the data from rodents linking caloric restriction to higher cognitive performance, (i.e., spatial memory and learning tests), a possible marker for aging.43 These findings from animal models are concordant with data from one study of an elderly population (ages > 75 years) in which an inverse relation between total energy intake and cognitive function was docu-mented.44 One possible mechanism of action for these effects is that caloric restriction results in fewer free radicals introduced into the body, resulting in less oxidative stress. This mechanism could specifically explain the associations with cognitive function since brain parenchyma consists of post-mitotic cells that would be more susceptible to oxidative damage.

4. Iron

The iron content of meats represents heme iron, while the iron content of plant foods is non-heme iron (Table 7.2). Data from human studies indicates that the bioavailability of heme iron (26% absorbed) is 10 times that of non-heme iron (2.5% absorbed).45 Thus, among humans, it is reasonable to assume that increased meat intake results in increased iron absorption relative to plant foods.

Although absorption of an adequate amount of iron is needed for normal body function, can excess iron absorption have pathologic effects? Iron has been identified as a possible risk factor for atherosclerotic diseases due to its pro-oxidant properties. Specifically, data from animal studies indicate that, once in circulation, ionic or free iron can promote the production of free radicals that can contribute to atherosclerosis by oxidizing low density lipoproteins (LDL)46 and also directly contribute to ischemic myocardial damage during reperfusion of the injured myocardium.47,48 Among 847 adults, Kiechl et al. have shown a positive correlation between serum ferritin and sonographically assessed carotid atheroscle-rosis.49 Also, data from a number of prospective studies implicate iron50-52 or heme iron53 as a risk factor for coronary heart disease, though there are some inconsistencies in the overall findings from population studies.54

Dietary iron that is not absorbed may also have pathologic effects. Babbs has hypothesized that an increased fecal concentration of iron can contribute to colon carcinogenesis by a mechanism whereby iron catalyzes the lumenal production of oxygen free radicals that can have a toxic and hyperproliferative effect on the colonic epithelium.55 Recent data from animal studies has specifically implicated heme iron in increased proliferation of the colonic epithelium.56 In this context, it is noteworthy that increased intake of red meats, a meat subtype that is high in heme iron content, has been linked to a higher risk of colon cancer57-60 and colorectal adenomas61 in prospective studies. Moreover, Willett has also reported a twofold increase in risk of colon cancer for high intake of liver, another meat subtype that is particularly high in heme iron content.57

5. Phosphorus

Meat products in the human diet contain, on average, substantially more phosphorus than calcium. The higher phosphorus-to-calcium ratio of meats as compared with plant foods (Table 7.2) raises the possibility that bone mass would be lower among meat eaters since higher phosphorus intake promotes binding and excretion of calcium that would otherwise be deposited in bone. Animal studies have shown, however, that the increased bone loss produced by an increased phosphorus intake was not entirely prevented by increasing calcium intake, but was prevented by parathy-

roidectomy.62,63 These data have been used to support the presence of another causal pathway whereby the increased dietary phosphorus-to-calcium ratio of meats contributes to secondary hyperparathyroidism — a condition that could potentially contribute to loss of bone mass. Specifically, when the homeostatic balance of serum calcium and phosphorus is altered in favor of increased phosphorus, there is a compensatory release of parathyroid hormone that activates increased calcium resorption from the bone. This mechanism suggests that the high serum phosphorus levels among meat-eaters should produce chronically increased calcium resorption from bone that could decrease skeletal mass and increase risk of osteoporosis and bone fractures.

Recent data from clinical studies have shown that even short-term (1-4 weeks) maintenance of high-phosphorus, low-calcium diets among women and men can produce mild hyperparathyroidism.64,65 In a cross-sectional study, Metz reported a significant negative correlation (R = -0.6 to -0.8) between dietary phosphorus intake and bone mineral content and bone mineral densities.66 Teegarden et al.67 have reported data indicating that the negative association between phosphorus and bone mineral density is complex, and may be dependent on intakes of calcium and protein. We are not aware of any large-scale prospective studies that relate phosphorus intake or meat intake to osteoporosis or bone fractures among adults.

6. Components of Meat Formed or Added During Processing, Storage, and Preparation

In developed nations, meat products in the diet have typically undergone a processing history that starts with the raising of livestock in commercial feedlots, continues with the preservation and storage of meat products obtained from that livestock, and ends with the preparation of the preserved or stored meat product as a dietary item. During this "processing history" there are commonly used methods of enhancing livestock growth and development, of prolonging the shelf-life of the meat product, and of cooking the meat product that can potentially result in the addition or formation of substances that remain in the ingested meat product. Some of these substances have been implicated in disease pathogenesis and are described in further detail in this section.

a. Exogenous Hormones, Antibiotics, and Feed Composition among Livestock

Recent media, political, and scientific attention has been given to a number of industrial practices commonly used in the raising of livestock in large commercial feedlots. These practices include the administration of hor mones and antibiotic preparations to the animals, and also the supplementation of animal feed with a meat-and-bone meal that contains rendered animal tissue.

Currently, about 70-90% of cattle in feedlots in the U.S. undergo a procedure in which a hormone implant is injected below the skin of their ear flap.68 Hormone implants have been commercialized and approved for use in livestock in the U.S. for the past 35 years. There are three naturally occurring mammalian hormones (estradiol, testosterone, progesterone) and two synthetic hormones (trenbolone acetate, zeranol) that are currently administered to cattle in the U.S. As of 1989, however, the European Union (EU) has banned use of all five hormones.69 The widespread use of these hormones in commercial feedlots is not surprising, given that hormone-implanted cattle experience an increased rate of weight gain while depositing less fat — effects that enable faster and more efficient production of lean meat.

Does the administration to cattle of these five growth hormones result in harmful increases in the hormone content of the ingested meats? Increased estradiol levels among humans have been implicated in cancers of the breast, uterus, and prostate.70 However, the FDA has indicated that the meat residue levels of estradiol and the two other naturally occurring hormones currently in use (progesterone, testosterone) produce a less than 1% increase in body stores of these hormones upon ingestion and thus should have little adverse effect.68 For the two synthetic hormone implants that are not produced by the body (trenbolone acetate, zeranol), the FDA has used findings from animal toxicology studies to set maximum allowable levels of the residues of these hormones in the ingested meat products.71 There are currently no data from large-scale population studies to support a direct causal link between the levels of these five hormones in meat and adverse health effects among humans.

When assessing the safety of meat from hormone-implanted cattle for the purpose of national and international policies, those who favor a ban on such implants often cite reports from the early 1970s that linked veal from calves treated with the growth hormone diethylstilbestrol to abnormal sexual development in infants and schoolchildren in Europe.72,73 This hormone has since been banned from use in cattle in Europe and the U.S. Also, there are some anecdotal reports that hormone implants misapplied to the muscle areas rather than the ear flap of cattle could result in higher hormone residue levels in the resulting meat products.74

In addition to the hormone implants, operators of commercial feedlots also administer antibiotics to cattle, pigs, and poultry to prevent infection and, by some unknown mechanism, enhance growth on less feed. In 1999, two reports in the New England Journal of Medicine documented instances in which antibiotic-resistant bacterial infections in humans were linked to the consumption of meats from livestock treated with antibiotics.75-76 In Denmark, Molbak et al.75 linked 25 culture-confirmed cases of antibiotic-resistant Salmonella infections to a specific swine herd that had been treated with fluoroquinolones. In Minnesota, Smith et al.,76 from the Minnesota Department of Public Health, documented a 17-fold rise in rates of qui-nolone-resistant Campylobacter jejuni infections since the 1994 FDA approval of quinolines in treating poultry infection. Taken together, these data implicate the use of livestock antibiotics in infectious human disease.

For many years, animal rendering plants have produced feed for cattle by a process of boiling down and making into feed animal tissue that usually comes from slaughterhouse scraps, dead farm animals, and animals from shelters. There is now good evidence that when cattle feed contains rendered animal tissue that is infected with a prion disease, this disease can be transmitted to the cattle that consume it.77 Prion diseases can affect animals and humans, can be transmitted within and between species, and are characterized by an accumulation in the brain of a protease-resistant protein known as a prion protein. Transmissible prion diseases among humans include Creutzfeldt-Jakob disease (CjD) and kuru, and among animals include scrapie and bovine spongiform encephalopathy (BSE). In 1986, an epidemic of BSE, commonly known as "mad cow disease," was identified among cattle in the U.K. that has been attributed to a prion strain from the sheep scrapie in the cattle feed.78,79 In 1996, a new variant of CjD was reported in the U.K. and has been attributed to the consumption of beef from cattle that were infected with BSE.80 As of January 31, 1999, there have been 39 cases of CjD in the U.K. and one in France.81 Data emerging from other European countries with similar cattle feed practices further support the possibility that contaminated feed is producing prion disease infection in livestock.82

b. Preservatives and Bacterial Toxins

Ingested meats have often been treated with additives to allow long-term preservation, and some of these additives have possible carcinogenic effects. Specifically, nitrates and nitrites have often been used as meat additives and these nitrosable compounds, similar to the nitrate derived from meat protein, have been implicated in colon and gastric carcinogenesis due to their contribution to endogenous formation of carcinogenic N-nitroso compounds.83 Salting and curing of meats is prevalent in some cultures, and this process is thought to contribute to gastric cancer by a mechanism whereby the salt irritates gastric epithelium and enhances the effects of other luminal carcinogens.84 Recent prospective evidence that links an increased risk of colon cancer to higher intake of processed meats may be identifying the independent effects of certain preservative methods.85

The methods of storing and handling uncooked meats in meat packing plants or by the consumer can allow for the introduction and replication of bacteria in the uncooked meat. One particular strain of the Escherichia Coli, E.coli O157:H7, can have particularly potent effects when it contaminates a meat product, and most commonly contaminates ground beef.86 E.coli O157:H7 produces a Shiga-like toxin that severely damages intestinal epithelial cells to the point of causing hemorrhaging. This type of E. coli poisoning of uncooked meats can therefore be quite lethal among young children, the elderly, or the immune compromised. Another bacteria that even more commonly contaminates uncooked meats is Salmonella. Sal-monellosis is the process by which the Salmonella-infected meat enters the intestine, replicates, and produces infection. Its severity varies and can be dependent on inoculating dose. The USDA recently reported the findings from 2 years of testing in large U.S. meat packing plants and found that the rate of Salmonella poisoning was as high as 30% for some ground meat products.87 Finally, a much less common larval infection can occur in uncooked meats, particularly pork and wild animals, that produces trichinosis. This disease can be fatal, but current prevalence is quite low (< 2%).

c. By-Products of Cooking

Certain cooking methods have long been implicated in the formation of carcinogens and mutagens in the cooked meat product that is ingested.83 Smoking, broiling, and grilling meats, or frying them in fat, have all been shown to produce biologically important amounts of benzo[a]pyrene and other polycyclic aromatic hydrocarbons.88 These compounds have been shown to have both carcinogenic and mutagenic effects that are stronger than N-nitroso compounds.30,31 Data supporting the even more potent carcinogenic and mutagenic effect of heterocyclic amines formed from cooked meat protein were summarized in the section on meat protein.

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