**4. Immune system**

If boron levels decrease in body, this decrease causes immune deficiency. However, higher and/or chronical exposure could have negative effects on immune system homeostasis [4].

Jin et al. conducted a study that showed that the effect of boron on the immune system in vivo is dose-dependent. They supplemented 0, 20, 40, 80, 160, 320, and 640 mg/L B in drinking water of rats (1.5, 3, 6, 12, 24, 48, and 96 mg/kg/bw) for 70 days. It was demonstrated that 20 and 40 mg/kg doses of B improved immune functions in the rats and increased the concentrations of serum IgG levels, splenic IFN-γ and IL-4 expressions, and the expression levels of CD3+, CD4+, and that they also proliferated cell nuclear antigen (PCNA) + cells. However, at such high concentrations as >48 mg/kg/bw, toxic effects on immune system were detected and immune activities were suppressed. At higher concentrations of IgG, IL10 levels and CD8+ cells were significantly found as decreasing. This is a good example of U-shaped dose– response effect. Both very low and very high concentrations could be associated with harmful effects on immune system [22].

Boron nitride nanotubes (BNNTs) engineered nanomaterials have superior electrical, chemical, and thermal properties, and they were planned to be used in the area of engineering applications such as lightweight and high-temperature ceramic components, flame retardants, etc. BNNTs' size could be <100nm in diameter and microns of length. Effects of mixture of BNNTs (BNNT-M) in vitro in THP-1 cells (human peripheral blood monocyte cell line) and in vivo pathogen-free, male C57BL/6J mice were evaluated by Kodali et al. The range of in vitro concentrations was 0–100 mg/ml and in vivo dose was 40 μg/mouse. BNNT induced cytotoxicity and cellular oxidative stress in THP-1 cells, being concentration-dependent. These results were in accordance with in vivo in the same study as increased lactate dehydrogenase levels in bronchoalveolar lavage, mitochondrial membrane potential loss. They demonstrated that cathepsin B, caspase 1, protein levels of IL-1b and IL-18 increased both in vitro and in vivo. These results indicated that BNNTs could increase acute inflammation and toxicity in vitro and in vivo [23].

The use of borax (Na2B4O2(H2O)10) as a food additive and its excessive consumption in recent years could result in serious toxic effects such as kidney damage. Higher borax exposure decreased immune cell numbers and increased sister chromatid exchange in blood immune lymphocyte cells [24].
