Lead toxicity in Flint, MI / Genetic susceptibility / Nutrients for reduction

[Ferrum Phos]

https://www.nature.com/articles/npjgenmed201618

A key factor, which almost certainly affects the range of susceptibility to lead poisoning, is a child’s genetic makeup. Current models for the neurotoxic effects of lead implicate the enzyme arylsulfatase A (ASA) as a particularly significant target of lead in the central nervous system (CNS).7. Reduced levels of cellular ASA by lead has been suggested to augment the other detrimental affects of the metal, resulting in the death or impaired function of oligodendroglia progenitor cells (OPCs) and lead to CNS dysfunction. Certain single-nucleotide polymorphisms (SNPs) of the gene for ASA (ARSA) cause greatly reduced levels of the enzyme with no obvious phenotype. One of these (Asn350Ser), first characterised in 1989,8 when homozygous, causes up to a 60% reduction in the intracellular levels of the enzyme.9 The homozygous presentation results in metachromatic leukodystrophy, leading to loss of developmental milestones in children and death at a young age. Low ASA activity in individuals with a heterozygous presentation can be identified via signs and symptoms, and it is suggested that these symptoms may be amplified when the individual is exposed to even low levels of environmental lead.4 Some symptoms of this heterozygous pseudodeficiency and environmental lead exposure may include: learning disabilities; behaviour problems' high blood pressure; tremors; seizure disorder; low sperm count and so on. This SNP is of particular relevance to the current situation in Flint, MI because a study conducted by one of us (J.Y.T.) and colleagues in 2002 of 107 African-American children in Detroit showed that this population had a gene frequency of ~0.45 for the Asn350Ser SNP, heterozygosity at this position often referred to as a pseudodeficiency. This frequency is much higher than what is seen in people of European ancestry (CEU=0.14) and higher frequency of this allele has been consistently reported in populations of African ancestry (ASW=0.36).10 These findings suggest that the Flint, MI population suffering lead exposure requires a more effective approach than simply measuring lead levels and setting a cutoff at 5 μg/dl. The question of the appropriate response to the interaction of genetics and lead toxicity was recently commented on by Poretz7 who stated ‘Identification of susceptible children for targeted concern and treatment would help alleviate the impact of the toxicant on the at-risk population.’ We agree strongly with this premise. Genotyping, followed by targeted intervention in Flint, of children who are at higher risk for lead poisoning should be carried out immediately, particularly for those who test below the poison mark. The current cutoff for clinical intervention at 5 μg/dl is inadequate and incorrect, especially for children who are carriers or homozygous for the Asn350Ser SNP.

Abstract: Genetic susceptibility to lead poisoning—A case report
Full text: http://medind.nic.in/iaf/t07/i2/iaft07i2p162.pdf

Genotype frequencies vary by geography and race. ALAD-2 is the rarer of the two alleles and has been associated with high blood lead levels. In comparison, African and Asian populations have a low ALAD-2 allele frequency with few or no ALAD-2 homozygotes found in such populations (9). It has been thought to increase the risk of lead toxicity by generating a protein that binds lead more tightly than the ALAD-1 protein. Other evidence suggests that ALAD-2 may confer resistance to the harmful effects of lead by sequestering lead and making it unavailable for pathophysiologic participation. (7) Recent studies have however, showed that individuals who are homozygous for the ALAD-1 allele have a higher cortical bone lead level. This implies that these individuals may have greater body burden of lead and may be at a higher risk of the longterm effects of lead.

https://www.lead.org.au/fs/Fact_sheet-Nutrients_that_reduce_lead_poisoning_June_2010.pdf

REDUCING LEAD ABSORPTION
For reducing lead absorption the key nutrients appear to be vitamin C, calcium, iron and, to a lesser degree, zinc and phosphorus. Dietary deficiencies in any of these can increase lead absorption, though supplementation of individuals with already high levels of these nutrients in their diet may not have much impact on lead absorption. Further, since these minerals compete with, or alter lead absorption during digestion, taking concentrated supplements at one point of time, unless you are deficient in that particular nutrient, may not affect continuing lead absorption, once the supplements have been processed through a particular stage of digestion. Vitamin D and folate (vitamin B9) can actually increase lead absorption, but have offsetting advantages: vitamin D can play a role in decreasing the quantity of lead stored in the bone, while folate seems to increase excretion more than it increases absorption.

INCREASING LEAD EXCRETION
For increasing lead excretion, two low toxicity B group vitamins have had widely demonstrated impacts in animal studies: B1 (thiamine or thiamin), which specifically increases excretion from the brain, and B9 (folate or folic acid); both are now compulsory additives in non–organic bread inside Australia. Vitamin B6 can increase lead excretion in animals, but there are few studies to draw conclusions from.

Vitamin C has chelating (metal binding) properties, and can increase lead excretion, but its impacts on excretion have not always been consistently demonstrated, particularly at higher lead levels. Pectin also has been linked to higher lead excretion, but questions have been raised as to its degree of effectiveness. For reducing blood lead levels, vitamin C, vitamin E, thiamine (B1), folate (B9) and iron have the strongest and most consistent blood lead links.

 

[Ferrum Phos]

https://www.lead.org.au/fs/Fact_sheet-Nutrients_that_reduce_lead_poisoning_June_2010.pdf

The role of vitamins in fighting lead poisoning

• Vitamin B1 has effects similar to vitamin C but does not modify as many indicators of lead impact, though it has strong impacts on increasing lead excretion from the brain and protecting brain function.
  
• Vitamin B6 and its derivative taurine can help protect and repair organs, including the brain, from lead-induced damage
  
• Folate and vitamin B12 function symbiotically in the body. Folate improves lead excretion, while both vitamins help in reducing lead-induced damage to the brain. Deficiencies of these two vitamins could worsen lead-induced anaemia (reducing red blood cell production) and add independent neurological damage.
  
• Higher levels of vitamin E are linked to lower blood lead levels to a similar degree as vitamin C, but supplementation carries significant risks; it is not recommended for pregnant women or individuals at risk of internal bleeding (e.g. at risk of stroke, on anti-coagulants, or vitamin K deficient). It protects cell membranes, notably of red blood cells, from lead-induced weakness and damage.
  
• Lead toxicity distorts the vitamin D metabolism that is necessary for the formation of bones. Adequate dietary levels of Vitamin D and calcium reduce this impact, and, in some cases, decrease the blood lead level along with lead deposition in bones, but probably only in the presence of sufficient levels of other minerals to replace the lead and allow bone formation.

The role of minerals in fighting lead poisoning

Many minerals compete with lead for both absorption and uptake by organs within the body.
Many aspects of lead toxicity relate to lead’s ability to replace key minerals: notably iron, calcium, and zinc, within the body.

• The replacement of calcium by lead in both the brain and nervous system is one of the primary paths of lead toxicity, so good levels of calcium reduce the capacity of lead to impair these functions. High calcium levels, when combined with adequate levels of nutrients such as magnesium and vitamin D, can potentially reduce the release of lead from the bone to the bloodstream and hence to organs of the body. There is strong evidence that calcium supplements reduce blood lead during pregnancy, thereby reducing lead concentrations in the newborn. The continuous maintenance of calcium levels is important for individuals with high lead exposures, to reduce brain and organ toxicity caused by the ongoing release of lead from the bone. However, calcium does not work in isolation, and good levels of phosphorus and magnesium may have supplementary effects on lead absorption, toxicity and bone stability. Due to increased bone turnover during pregnancy, lactation and menopause, this is of particular importance to women.
  
• Iron functions similarly to calcium, competing with lead for absorption in the gut and uptake within the body. Good levels of iron can reduce lead-induced brain and kidney damage, while lessening the impact of lead-induced anaemia. Iron deficiency, which significantly increases lead absorption, is the most common nutrient deficiency, found predominantly among pre-menopausal women and children. Iron deficiency has independent impacts on the brain and blood cells, which can exacerbate lead impacts, particularly in children.
  
• The impact of zinc is similar in nature to iron and calcium, but more muted, with no strong evidence of impacts on blood lead levels, and mixed impacts on organs and bones. However, it appears to significantly lessen lead impacts on the liver, kidneys, testes and especially the brain, an organ with very high concentrations of zinc.
  
• From a small handful of mostly animal studies, there are indications that magnesium may reduce lead retention in blood and tissues, and may ameliorate lead-induced hypertension.
  
• Selenium combines with lead to form non-toxic compounds, potentially reducing lead absorption and toxicity.

The role of amino acids and other nutrients in fighting lead poisoning

Other nutrients that have influence on lead level are methionine, glycine, curcumin, methionine, carotene and pectin, and nutrients found in garlic.

• From animal studies there are indications that garlic could reduce blood and tissue lead levels, probably because it contains a wide range of sulfur-based compounds essential for amino acid construction and antioxidant function, including methionine.
  
• Methionine could repair some lead-induced learning and memory decline and help protect against liver and kidney damage.
  
• Curcumin (an active ingredient in turmeric) and glycine could be protective against lead-induced brain damage.
  
• Cysteine (which can be replaced using methionine), glutamic acid or glutamate and glycine are used to manufacture glutathione, a major antioxidant, which, when depleted by lead can increase lead toxicity in the organs, particularly the brain and liver.
  
• High serum (blood) carotene levels have been linked to lower blood lead levels, but there is no real evidence, as yet, that the relationship is causative.