The I2C pins on the Arduino Mega 2560 board are 100% reliable, but you have to use them correctly.
The Wire library could halt when something is wrong with the hardware I2C bus. In that case the sketch stops. The Wire library should have timeouts programmed in case something is wrong with the hardware, but sadly it doesn't have timeouts.
The hardware I2C bus on the Arduino Mega 2560 board is a 5V I2C bus, because the Arduino Mega 2560 has 10k pullup resistors to 5V for SDA and SCL.
The wires for I2C can only be short. Long wires will not work.
The worst thing is when SDA and SCL are in a flat ribbon cable next to each other. The crosstalk between SDA and SCL will make the I2C very unreliable.
Because it is a 5V I2C bus, you may not connect 3.3V sensors to that 5V I2C bus. In that case you need a level converter.
The total value of all pullup resistors in parallel should not be too high (more sensitive for electrical noise, longer wires are not possible) and not be too low. The I2C specificiation is maximum 3 mA pulling of down current to get the signal low.
Everything that is connected to the I2C bus must have proper power supply. If one sensor has a power supply that fails, then that sensor will probably pull down the SCL and SDA signals.
A test with a breadboard might fail, due to bad contacts of the breadboard.
The Arduino Wire library is often used in a wrong way.
If one of the sensors is an Arduino board as a I2C slave, then the code for the slave must be done right, because there are many ways to do it wrong.
You could check the return value of every Wire.endTransmissions for an error, and check every return value of Wire.requestFrom for the amount of data that is received.
If you tell us everything about the sensors, the wires (with photos), the logic level converters, the sketch, and so on, then we can tell you what the problem is.